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Lipoprotein subclass analysis by immunospecific density  

E-print Network

Bio-medical Company). The apo C-1-depleted serum is removed by centrifugation and all apo C-1-containing lipoproteins are released from the Sepharose beads at pH 2. The apo C-1-depleted sample and the apo C-1-containing sample were ultracentrifuged...

Lester, Sandy Marie



Are post-treatment low-density lipoprotein subclass pattern analyses potentially misleading?  

Microsoft Academic Search

BACKGROUND: Some patients administered cholesterol-lowering therapies may experience an increase in the proportion of small LDL particles, which may be misinterpreted as a worsening of atherosclerotic coronary heart disease risk. This study assessed the lipid effects of adding ezetimibe to atorvastatin or doubling the atorvastatin dose on low-density lipoprotein cholesterol (LDL-C) levels (and the cholesterol content of LDL subclasses), LDL

Harold Bays; Scott Conard; Lawrence A Leiter; Steven Bird; Erin Jensen; Mary E Hanson; Arvind Shah; Andrew M Tershakovec



Fluorometric sedimentation equilibrium for lipoprotein sub-class analysis.  

E-print Network

fluorescent probe for analysis, and modern statistical methods for classification of heart disease risk. Sub-classes of lipoproteins are analyzed based on their density from the fluorescent lipoprotein density profile. The application of linear discriminant...

Henriquez, Ronald Rene



Identification of multiple subclasses of plasma low density lipoproteins in normal humans  

Microsoft Academic Search

Density gradient ultracentrifugation of low density lipoproteins (LDL) from 12 normal subjects showed multiple, distinct isopycnic bands. Each band could be assigend to one of four density intervals and the boundaries of these intervals were consistent among all the subjects. Analytic ultracentrifuge flotation (S\\/sub f\\/°) rates were assigned to the four density intervals, and there was a strong correlation between

Ronald M. Krauss; David J. Burke



Effect of fenofibrate therapy and ABCA1 polymorphisms on high-density lipoprotein subclasses in the Genetics of Lipid Lowering Drugs and Diet Network  

Microsoft Academic Search

Background: Previous studies have shown that ATP-binding cassette transporter 1 (ABCA1) polymorphisms associated with increased ABCA1 expression result in increased small HDL (high-density lipoprotein) subclass particle concentration. This study examines the effect of treatment with fenofibrate, a drug known to bind peroxisome proliferator-activated receptor alpha (PPAR?) which increases the expression of ABCA1 gene, on lipoprotein subclass profiles of individuals stratified

Michael Y. Tsai; Jose M. Ordovas; Na Li; Robert J. Straka; Naomi Q. Hanson; Valerie L. Arends; Donna Arnett



The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B  

SciTech Connect

To better define the role of environmental factors on LDL phenotypic expression, the authors determined LDL patterns in patients with acquired immunodeficiency syndrome (AIDS), and infection characterized by hypertriglyceridemia and weight loss. Similar to previous studies, plasma triglyceride levels were increased, whereas plasma cholesterol, LDL cholesterol, and HDL cholesterol levels were decreased in the AIDS subjects compared to those in age-matched controls. The percentage of AIDS subjects with the LDL B phenotype was increased 2.5-fold, demonstrating an increased prevalence of the LDL B phenotype in an acquired form of hypertriglyceridemia. For each LDL phenotype in AIDS, serum triglyceride levels were higher than the same phenotypic pattern in controls, with the most marked elevations in triglycerides found in AIDS subjects with the LDL B phenotype. In contrast to what was observed in controls, HDL cholesterol levels were decreased in all AIDS subjects and were unrelated to LDL pattern. Total and LDL cholesterol levels were higher in controls with the LDL B phenotype than in those with the LDL A phenotype, but there was no difference in total and LDL cholesterol in AIDS subjects with LDL B compared to A. On multiple regression analysis in subjects with AIDS, plasma triglyceride levels, age, and HDL cholesterol all contribute to the occurrence of the LDL B phenotype, but elevations in plasma triglyceride levels are the strongest independent predictor. Body mass index was not a predictor of LDL B phenotype in AIDS. These results suggest that disturbances in triglyceride metabolism that are caused by AIDS lead to the appearance of the LDL subclass B phenotype and provide further evidence that environmental or disease states that perturb lipid metabolism can produce an increased prevalence of the LDL B phenotype. 35 refs., 1 fig., 5 tabs.

Feingold, K.R.; Krauss, R.M.; Pang, M.; Doerrler, W.; Jensen, P.; Grunfeld, C. (Univ. of California, San Francisco (United States) Lawrence Berkeley Lab., CA (United States))



Effects of extended-release niacin on lipoprotein subclass distribution  

Microsoft Academic Search

The efficacy of extended-release niacin (niacin ER) on lipoprotein subclasses was evaluated in patients with primary hypercholesterolemia using a proton nuclear magnetic resonance method. Paired plasma samples collected at baseline and after 12 weeks’ treatment with niacin ER 1,000 (n = 21) or 2,000 (n = 20) mg\\/day or placebo (n = 19) were available for 60 eligible patients from

John M Morgan; David M Capuzzi; Ronnie I Baksh; Charles Intenzo; Christina M Carey; Dana Reese; Kalen Walker



Effects of cardiovascular lifestyle change on lipoprotein subclass profiles defined by nuclear magnetic resonance spectroscopy  

PubMed Central

Background Low-density lipoprotein (LDL) cholesterol lowering is a primary goal in clinical management of patients with cardiovascular disease, but traditional cholesterol levels may not accurately reflect the true atherogenicity of plasma lipid profiles. The size and concentration of lipoprotein particles, which transport cholesterol and triglycerides, may provide additional information for accurately assessing cardiovascular risk. This study evaluated changes in plasma lipoprotein profiles determined by nuclear magnetic resonance (NMR) spectroscopy in patients participating in a prospective, nonrandomized lifestyle modification program designed to reverse or stabilize progression of coronary artery disease (CAD) to improve our understanding of lipoprotein management in cardiac patients. Results The lifestyle intervention was effective in producing significant changes in lipoprotein subclasses that contribute to CAD risk. There was a clear beneficial effect on the total number of LDL particles (-8.3%, p < 0.05 compared to matched controls), small dense LDL particles (-9.5%, p < 0.05), and LDL particle size (+0.8%; p < 0.05). Likewise, participants showed significant improvement in traditional CAD risk factors such as body mass index (-9.9%, p < 0.01 compared to controls), total cholesterol (-5.5%, p < 0.05), physical fitness (+37.2%, p < 0.01), and future risk for CAD (-7.9%, p < 0.01). Men and women responded differently to the program for all clinically-relevant variables, with men deriving greater benefit in terms of lipoprotein atherogenicity. Plasma lipid and lipoprotein responses to the lifestyle change program were not confounded by lipid-lowering medications. Conclusion In at risk patients motivated to participate, an intensive lifestyle change program can effectively alter traditional CAD risk factors and plasma lipoprotein subclasses and may reduce risk for cardiovascular events. Improvements in lipoprotein subclasses are more evident in men compared to women. PMID:19563671

Decewicz, David J; Neatrour, David M; Burke, Amy; Haberkorn, Mary Jane; Patney, Heather L; Vernalis, Marina N; Ellsworth, Darrell L



Autoantibodies against oxidized low density lipoproteins (oxLDL): characterization of antibody isotype, subclass, affinity and effect on the macrophage uptake of oxLDL.  

PubMed Central

Circulating antibodies against oxLDL are present in several inflammatory and autoimmune conditions. Such antibodies are also present in patients with atherosclerosis, although the pathogenic significance of the antibodies is still not known. We have characterized the antibodies with regard to isotype, subclass, affinity and effect on macrophage uptake of oxLDL. Antibodies of IgG and IgM isotype were most common and found both in patients with atherosclerosis and in normal individuals. The subclass of IgG antibodies was mainly IgG2 and IgG3. Scatchard analyses of IgG and IgM antibodies showed that IgG antibodies were heterogeneous with regard to affinity, whereas only one population of high-affinity antibodies was found in the IgM antibody population. The high-affinity populations had an average equilibrium constant (K0) of 8.84 x 10(9) M-1 for IgG antibodies and of 1.65 x 10(9) M-1 for IgM antibodies. Incubation of 125I-oxLDL with purified IgG and IgM from sera with high amounts of antibodies enhanced the uptake of 125I-oxLDL in the monocyte-like U937 cell line. Antibody preparations from sera containing no anti-oxLDL antibodies and from sera with antibodies against LDL had less effect on this uptake. The increased uptake was competitively decreased by adding unlabelled oxLDL. This study shows that antibodies against oxLDL are mainly IgG2, IgG3 and IgM. Both IgG and IgM antibodies have a high affinity for the antigen and increase the uptake of oxLDL in a monocyte-like cell line. PMID:7554386

Wu, R; Lefvert, A K



Hypertriglyceridemia and unusual lipoprotein subclass distributions associated with late pregnancy  

SciTech Connect

In the human adult population elevated plasma triglyceride (TG) levels are associated with decreased high density lipoprotein-cholesterol (HDL-C) levels and decreased HDL and LDL particle sizes. Late pregnancy is a hypertriglyceridemic state where little is known about LDL and HDL subpopulation distribution. Plasma lipids, apolipoproteins (apo) and lipoprotein subpopulations were examined in 36 pregnant women at 36 wk pregnancy and 6 wk postpartum and correlated with HDL and LDL size. There was a significant decrease in LDL diameter at 36 wk pre, 25 {plus minus} 0.7 nm compared, with 6 wk post, 26.4 {plus minus} 0.8 nm. A total of 97% of the 36 wk pre subjects had small dense LDL which paralleled increases in apoB concentration. Unlike LDL HDL at 36 wks pre showed a significant increase in larger sized particles where HDL{sub 2b} predominated. There was a positive correlation between HDL{sub 2b} mass and apoAl and HDL-C concentrations. Late pregnancy is a metabolic state where the predominance of large, HDL{sub 2b} particles is discordant with the predominance of small LDL and elevated TG. This annual metabolic pattern may in part be due to hormonal changes occurring in late pregnancy.

Forte, T.M.; Kretchmer, N.; Silliman, K. (Lawrence Berkeley Lab., CA (United States))



Lipoprotein subclasses in genetic studies: The Berkeley Data Set  

SciTech Connect

Data from the Berkeley Data Set was used to investigate familial correlations of HDL-subclasses. Analysis of the sibling intraclass correlation coefficient by HDL particle diameter showed that sibling HDL levels were significantly correlated for HDL{sub 2b}, HDL{sub 3a} and HDL{sub 3b} subclasses. The percentage of the offsprings` variance explained by their two parents. Our finding that parents and offspring-have the highest correlation for HDL{sub 2b} is consistent with published reports that show higher heritability estimates for HDL{sub 2} compared with HDL{sub 3}{minus} cholesterol.

Krauss, R.M.; Williams, P.T.; Blanche, P.J.; Cavanaugh, A.; Holl, L.G. [Lawrence Berkeley Lab., CA (United States); Austin, M.A. [Washington Univ., Seattle, WA (United States). Dept. of Epidemiology



Lipoprotein Subclasses Determined by Nuclear Magnetic Resonance Spectroscopy and Coronary Atherosclerosis in Patients with Rheumatoid Arthritis  

PubMed Central

Objective Patients with rheumatoid arthritis (RA) are at increased risk of atherosclerosis, but routine lipid measurements differ little from those of people without RA. We examined the hypothesis that lipid subclasses determined by nuclear magnetic resonance spectroscopy (NMR) differed in patients with RA compared to controls and are associated with disease activity and the presence of coronary-artery atherosclerosis. Methods We measured lipoprotein subclasses by NMR in 139 patients with RA and 75 control subjects. Lipoproteins were classified as large LDL (diameter range: 21.2-27.0 nm), small LDL (18.0-21.2 nm), large HDL (8.2-13.0 nm), small HDL (7.3-8.2 nm), and total VLDL (?27 nm). All subjects underwent an interview and physical examination; disease activity was quantified by the 28 joint disease activity score (DAS28) and coronary artery calcification (CAC) was measured with electron beam computed tomography. Results Concentrations of small HDL particles were lower in patients with RA (18.2±5.4 nmol/L) than controls (20.0±4.4 nmol/L), P=0.003. In patients with RA, small HDL concentrations were inversely associated with DAS28 (rho=-0.18, P=0.04) and CRP (rho=-0.25, P=0.004). Concentrations of small HDL were lower in patients with coronary calcification (17.4±4.8 nmol/L) than in those without (19.0±5.8 nmol/L), P=0.03. This relationship remained significant after adjustment for the Framingham risk score and DAS28 (P=0.025). Concentrations of small LDL particles were lower in patients with RA (1390±722 nmol/L) than in control subjects (1518±654 nmol/L), P=0.05, but did not correlate with DAS28 or CAC. Conclusions Low concentrations of small HDL particles may contribute to increased coronary atherosclerosis in patients with RA. PMID:20516025

Chung, Cecilia P.; Oeser, Annette; Raggi, Paolo; Sokka, Tuulikki; Pincus, Theodore; Solus, Joseph F.; Linton, MacRae F.; Fazio, Sergio; Stein, C. Michael



Intima-media thickness of the carotid artery and the distribution of lipoprotein subclasses in men aged 40-49 between whites in the U.S. and the Japanese in Japan for the ERA JUMP Study  

PubMed Central

In men in the post World War II birth cohort, i.e., men aged 40–49, whites in the United States (U.S.) had significantly higher levels of intima-media thickness of the carotid arteries (IMT) than the Japanese in Japan. The difference remained after adjusting for traditional risk factors. Primary genetic effects are unlikely, given the degree to which IMT is increased in the Japanese who migrated to the U.S. We investigated whether the differences in the distributions of lipoprotein subclasses explain the difference in IMT between the two populations. We examined population-based samples of 466 randomly-selected men aged 40–49 (215 whites from Allegheny County, U.S., and 241 Japanese from Kusatsu, Japan). Lipoprotein subclasses were determined by nuclear magnetic resonance (NMR) spectroscopy. The whites had significantly higher levels of large very-low-density-lipoprotein particles and significantly lower levels of large high-density-lipoprotein particles than the Japanese, whereas the two populations had similar levels of small low-density-lipoprotein particles. The two populations had similar associations of IMT with NMR lipoproteins. Adjusting for NMR lipoproteins did not attenuate the significant difference in IMT between the two populations (0.671 ± 0.006 for the whites and 0.618 ± 0.006 mm for the Japanese, P=0.01, mean (standard error)). Differences in the distributions of NMR lipoproteins between the two populations did not explain the higher IMT in the whites. PMID:18191046

Sekikawa, Akira; Ueshima, Hirotsugu; Sutton-Tyrrell, Kim; Kadowaki, Takashi; El-Saed, Aiman; Okamura, Tomonori; Takamiya, Tomoko; Ueno, Yoshiki; Evans, Rhobert W.; Nakamura, Yasuyuki; Edmundowicz, Daniel; Kashiwagi, Atsunori; Maegawa, Hiroshi; Kuller, Lewis H.



Narrowing Sex Differences in Lipoprotein Cholesterol Subclasses Following Mid-Life: The Very Large Database of Lipids (VLDL-10B)  

PubMed Central

Background Women have less risk of atherosclerotic cardiovascular disease compared with men up until midlife (ages 50 to 60), after which the gap begins to narrow post menopause. We hypothesized that the average lipid profile of women undergoes unfavorable changes compared with men after midlife. Methods and Results We examined lipids by sex and age in the Very Large Database of Lipids 10B (VLDL 10B) study. The analysis included 1 350 908 unique consecutive patients clinically referred for lipoprotein testing by density gradient ultracentrifugation from 2009 to 2011. Ratio variables were created for density subclasses of LDL?C, HDL?C, and VLDL?C (LLDR, LHDR, LVDR, respectively). Men showed higher median LDL?C values than women for ages 20 to 59, with the greatest difference in their 30s: 146 mg/dL in men versus 130 mg/dL in women. In contrast, women consistently had higher values after midlife (age 60), for example ages 70 to 79: 129 mg/dL in women versus 112 mg/dL in men. After age 50, women had higher LDL?C each decade, for example 14% higher from their 30s to 50s, while HDL?C concentrations did not differ. Women had more buoyant LDL?C and HDL?C (lower LLDR and LHDR) than men at all ages but the gap closed in higher age groups. In contrast, women had a generally denser VLDL?C (higher LVDR) leading into midlife, with the gap progressively closing in higher age groups, approximating that of men in their 60s and 70s. Conclusion The narrowing sex differential in cardiovascular disease risk after midlife is mirrored by a higher total atherogenic lipoprotein cholesterol burden in women and a closer approximation of the less favorable density phenotype characteristic of men. PMID:24755154

Swiger, Kristopher J.; Martin, Seth S.; Blaha, Michael J.; Toth, Peter P.; Nasir, Khurram; Michos, Erin D.; Gerstenblith, Gary; Blumenthal, Roger S.; Jones, Steven R.



Effect of L-Carnitine on the Serum Lipoproteins and HDLC Subclasses in Hemodialysis Patients  

Microsoft Academic Search

Aims: Following carnitine administration a decrease in plasma levels of triglyceride (TG) and increase in total high-density lipoprotein cholesterol (HDL-C) has been reported. Our hypothesis was that it also improves the HDL2\\/HDL3 ratio, symptomatic intradialytic hypotension, and anemia in hemodialysis (HD) patients. Methods: Forty HD patients with a mean (± SD) age of 53 ± 13 years were treated with

H. Argani; M. Rahbaninoubar; A. Ghorbanihagjo; Z. Golmohammadi; N. Rashtchizadeh



Familial apolipoprotein Al and apolipoprotein CIII deficiency: subclass distribution, composition, and morphology of lipoproteins in a disorder associated with premature atherosclerosis  

SciTech Connect

Lipoprotein classes isolated from the plasma of two patients with apolipoprotein AI (apo AI) and apolipoprotein CIII (apo CIII) deficiency were characterized and compared with those of healthy, age- and sex-matched controls. The plasma triglyceride values for patients 1 and 2 were 31 and 51 mg/dl, respectively, and their cholesterol values were 130 and 122 mg/dl, respectively; the patients, however, had no measurable high density lipoprotein (HDL)-cholesterol. Analytic ultracentrifugation showed that patients' S/sub f//sup 0/ 0-20 lipoproteins posses a single peak with S/sub f//sup 0/ rates of 7.4 and 7.6 for patients 1 and 2, respectively, which is similar to that of the controls. The concentration of low density lipoprotein (LDL) (S/sub f//sup 0/ 0-12) particles, although within normal range (331 and 343 mg/dl for patients 1 and 2, respectively), was 35% greater than that of controls. Intermediate density lipoproteins (IDL) and very low density lipoproteins (VLDL) (S/sub f//sup 0/ 20-400) were extremely low in the patients. HDL in the patients had a calculated mass of 15.4 and 11.8 mg/dl for patients 1 and 2, respectively. No HDL could be detected by analytic ultracentrifugation, but polyacrylamide gradient gel electrophoresis (gge) revealed that patients possessed two major HDL subclasses: (HDL/sub sb/)/sub gge/ at 11.0 nm and (HDL/sub 3b/)/sub gge/ at 7.8 nm. The major peak in the controls (HDL/sub 3a/)/sub gge/, was lacking in the patients.

Forte, T.M.; Nichols, A.V.; Krauss, R.M.; Norum, R.A.



Impaired metabolism of high density lipoprotein in uremic patients  

Microsoft Academic Search

Impaired metabolism of high density lipoprotein in uremic patients. We measured lipoproteins, apolipoproteins, lipoprotein lipase (LPL), hepatic triglyceride lipase (HTGL), lecithin: cholesterol acyltransferase (LCAT) and parameters of calcium metabolism to evaluate the roles of these enzymes and hypertriglyceridemia for impaired high-density lipoprotein (HDL) metabolism in chronic renal failure, and to examine the impact of altered calcium homeostasis on the lipoprotein-regulating

Tetsuo Shoji; Yoshiki Nishizawa; Hiroshi Nishitani; Makoto Yamakawa; Hirotoshi Morii



In vitro Catabolism of very low density lipoproteins from horse ( Equus caballus) by the action of autologous lipoprotein lipase  

Microsoft Academic Search

Incubation of equine very low density lipoproteins with lipoprotein lipase isolated from horse postheparin plasma resulted in the formation of lipoproteins of a higher density. Lipoproteins isolated after incubation and plasma lipoproteins had a different chemical composition and triacylglycerol fatty acid pattern. In vitro-obtained low density lipoproteins contained substantially more phospholipids and triacylglycerols but significantly less cholesteryl esters than native

Carolin S. Stachel; Hubert O. Weik



Original article Serum total cholesterol, high-density lipoprotein-  

E-print Network

Original article Serum total cholesterol, high-density lipoprotein- cholesterol and triglyceride- copherol provided daily in equimolar amounts on total cholesterol, high-density lipoprotein- cholesterol sources resulted in no overall treatment effects for total cholesterol, triglycerides or high density

Paris-Sud XI, Université de


Mechanistic studies of high-density lipoproteins  

Microsoft Academic Search

There is increasing evidence that high-density lipoprotein (HDL) and its subfractions are protective against atherosclerotic cardiovascular disease. Physical exercise, weight reduction, smoking cessation, diabetes mellitus control, and specific drugs, including niacin, fibrates, and estrogens, are effective methods to increase HDL levels. Niacin is the oldest and most powerful clinical agent for raising HDL levels. Niaspan, an extended-release niacin formulation, is

MotiL Kashyap



Reconstitution of the trypanolytic factor from components of a subspecies of human high-density lipoproteins  

Microsoft Academic Search

Trypanosoma brucei brucei is non-infectious to man due to the sensitivity of these parasites to the lytic activity of normal human serum. Apolipoproteins (apo) have been purified, under non-denaturing conditions, from the subclass of human high-density lipoprotein (HDL), termed trypanosome lytic factor (TLF), which is responsible for the cytotoxicity of human serum to T. b. brucei. The TLF apolipoproteins were

Ewan M. Tytler; D. Ray Moore; Mark A. Pierce; Kristin M. Hager; Jeffrey D. Esko; Stephen L. Hajduk



Modulation of High-Density Lipoprotein Cholesterol Metabolism and Reverse Cholesterol Transport  

Microsoft Academic Search

Low high-density lipoprotein (HDL)-cholesterol (C) is an important risk factor for coronary heart disease. In vitro, HDL exerts several potentially anti-atherogenic effects including reverse cholesterol transport (RCT) from peripheral cells to the liver. Hence, raising HDL-C has become an interesting target for anti-atherosclerotic drug therapy. Levels of HDL-C and the composition of HDL subclasses in plasma are regulated by apolipoproteins,

M. Hersberger; A. Eckardstein


A step towards quantitative lipoprotein density profiling analysis: applied Rayleigh scattering  

E-print Network

to lipoprotein subclasses is exposed. Lipoprotein diameters are estimated from Rayleigh imaged serum profiles and the estimations are confirmed through secondary size analysis achieved by dynamic light scattering instrumentation. In addition to Rayleigh...

Nowlin, Michael



Effect of niacin and atorvastatin on lipoprotein subclasses in patients with atherogenic dyslipidemia  

Microsoft Academic Search

This study was conducted to determine the efficacy of atorvastatin and niacin on lipoprotein subfractions in patients with atherogenic dyslipidemia. This was a multicenter, randomized, open-label, parallel-design study of patients with total cholesterol >200 mg\\/dl, triglycerides between 200 and 800 mg\\/dl, and apolipoprotein B >110 mg\\/dl. Patients were randomly assigned to atorvastatin 10 mg or immediate release niacin 3,000 mg

James M McKenney; Lisa S McCormick; Ernst J Schaefer; Donald M Black; Michael L Watkins



Abnormal high density lipoproteins in cerebrotendinous xanthomatosis  

SciTech Connect

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

Shore, V. (Lawrence Livermore Lab., CA); Salen, G.; Cheng, F.W.; Forte, T.; Shefer, S.; Tint, G.S.



Regulation of high density lipoprotein levels  

SciTech Connect

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

Krauss, R.M.



Developing High Performance Lipoprotein Density Profiling for Use in Clinical Studies Relating to Cardiovascular Disease  

PubMed Central

Early detection of the beginning stage of cardiovascular disease (CVD) is an approach to prevention because the process is reversible at this stage. Consequently, several methods for screening for CVD have been introduced in recent years incorporating different analytical methods for characterizing the population of blood-borne lipoprotein subclasses. The gold standard method for lipoprotein subclassification is based on lipoprotein density measured by sedimentation equilibrium using the ultracentrifuge. However, this method has not been adopted for clinical studies because of difficulties in achieving the precision required for distinguishing individuals with and without CVD particularly when statistical classification methods are used. The objective of this study was to identify and improve the major factors that influence the precision of measurement of lipoprotein density profile by sedimentation equilibrium analysis and labeling with a fluorescent probe. The study has two phases, each contributing to precision. The first phase focuses on the ultracentrifugation-related variables, and the second phase addresses those factors involved in converting the fluorescent lipoprotein density profile to a digital format compatible with statistical analysis. The overall improvement in precision was on the order of a factor of 5, sufficient to be effectively applied to ongoing classification studies relating to CVD risk assessment. PMID:21970640



The antiatherogenic role of high-density lipoprotein cholesterol  

Microsoft Academic Search

Landmark clinical studies in the past 5 years that demonstrated diminished mortality and first coronary events following lowering of low-density lipoprotein (LDL) cholesterol stimulated considerable interest in the medical community. Yet, high-density lipoprotein (HDL) cholesterol, which transports circulating cholesterol to the liver for clearance, clearly also exerts antiatherogenic effects. The Framingham Heart Study produced compelling epidemiologic evidence indicating that a

Peter O. Kwiterovich



Reaching low density lipoprotein cholesterol targets.  


Abstract Cardiovascular disease is a major health problem and within the leading causes of death worldwide. Low-density lipoprotein cholesterol (LDL-C) is strongly associated with the development and progression of cardiovascular disease and is among the main targets of lipid lowering therapy. Despite the various lipid lowering agents for the management of hyperlipidemia, a significant number of patients do not reach their LDL-C target goals. Data from studies in various world regions identify an often poor achievement of LDL-C goals, especially in high risk patient groups. The causes of this suboptimal management of hyperlipidemia are multifactorial and measures should be taken in order to identify and address these shortcomings in dyslipidemia therapy. PMID:25055191

Rizos, Christos V; Barkas, Fotios; Elisaf, Moses S



Lipoprotein (a), low-density, intermediate-density lipoprotein, and blood pressure in a young male population  

Microsoft Academic Search

Both hypercholesterolemia and hypertension are risk factors for atherosclerotic vascular disease, and elevated cholesterol levels occur more frequently than expected in patients with hypertension. Elevated levels of intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL) were shown to be atherogenic, and LDL, comprising the major cholesterol-carrying fraction in human plasma, are structurally related to lipoprotein (a) [Lp(a)], a further risk factor

A. Steinmetz; A. Kirklies; G. Schlosser; W. Cassel; J. H. Peter; K. Ehlenz; J. R. Schäfer; P. v. Wichert; H. Kaffarnik



Physicochemical characterization of Rhesus low density lipoproteins.  


The serum low density lipoprotein (LDL; p 1.019-1.050 g/ml) of the normal Macaca mulatta monkey (rhesus), kept on a low-fat Purina primate chow diet, was isolated by ultracentrifugal flotation, and its physicochemical properties were compared with those previously reported for human LDL. Rhesus LDL was found to be chemically similar to human LDL. The values for the sedimentation (S25, w-O) and diffusion (D25,w-O) coefficients were 7.09 S and 2.50 times 10- minus-7 cm-2 sec- minus-1, respectively. The intrinsic viscosity was 3.40 ml g- minus-1. The partial specific volume of rhesus LDL, determined in an Anton Paar precision density meter, was 0.960 ml g- minus-1. Molecular weights, calculated from a combination of S-O and D-O and of S-O and [n], were in agreement with the weight-average molecular weight, Mw, of 2.29 times 10-6 obtained by high-speed sedimentation equilibrium. In addition, a Z-average molecular weight, Mz, of 2.73 times 10-6 was calculated because curvature in the graphs of log c vs. r-2 indicated that rhesus LDL was heterogeneous. From the frictional ratio of 1.02, a maximum hydration of 0.1 g of H2O/g of lipoprotein was obtained. On electron micrographs, rhesus LDL appeared spherical with a mean diameter of 196 A, which was substantiated by hydrodynamic analysis. PMID:164895

Fless, G M; Scanu, A M



21 CFR 866.5600 - Low-density lipoprotein immunological test system.  

Code of Federal Regulations, 2010 CFR

...2010-04-01 2010-04-01 false Low-density lipoprotein immunological test system...Test Systems § 866.5600 Low-density lipoprotein immunological test system. (a) Identification. A low-density lipoprotein immunological...



21 CFR 866.5600 - Low-density lipoprotein immunological test system.  

Code of Federal Regulations, 2011 CFR

...2011-04-01 2011-04-01 false Low-density lipoprotein immunological test system...Test Systems § 866.5600 Low-density lipoprotein immunological test system. (a) Identification. A low-density lipoprotein immunological...



Negatively Cooperative Binding of High-Density Lipoprotein to the HDL Receptor SR-BI  

E-print Network

Scavenger receptor class B, type I (SR-BI), is a high-density lipoprotein (HDL) receptor, which also binds low-density lipoprotein (LDL), and mediates the cellular selective uptake of cholesteryl esters from lipoproteins. ...

Xu, Shangzhe


Serum n-6 fatty acids and lipoprotein subclasses in middle-aged men: the population-based cross-sectional ERA-JUMP Study123  

PubMed Central

Background: The associations of serum omega-6 (n?6) fatty acids with lipoprotein subclasses at the population level are uncertain. Objective: We aimed to examine associations between major n?6 fatty acids [ie, linoleic acid (LA, 18:2n?6) and arachidonic acid (AA, 20:4n?6)] and the lipoprotein subclasses VLDL, LDL, and HDL. Design: We conducted a cross-sectional study in 1098 participants using population-based data from US white, Japanese American, Japanese, and Korean men aged 40–49 y. Serum fatty acids were analyzed by capillary gas-liquid chromatography. Lipoprotein subclasses were measured by nuclear magnetic resonance spectroscopy. Multiple linear regression models as a function of each fatty acid were used after adjustment for age, population, body mass index, pack-years of smoking, alcohol consumption, diabetes, hypertension, and omega-3 (n?3) and trans fatty acids. Results: Serum LA was inversely associated with large VLDL (? = ?0.62, P < 0.001), total LDL (? = ?22.08, P < 0.001), and small LDL (? = ?31.89, P < 0.001) particle concentrations and VLDL size (? = ?0.72, P < 0.001). Serum LA was positively associated with large HDL particle concentration (? = 0.21, P < 0.001) and HDL size (? = 0.03, P < 0.001). The patterns of association of AA with large VLDL and large HDL particle concentrations were comparable with those of LA. Conclusions: At the population level, higher serum concentrations of LA were significantly associated with lower concentrations of total LDL particles. Higher serum concentrations of LA and AA were significantly associated with a lower concentration of large VLDL particles and a higher concentration of large HDL particles. These associations were consistent across the population groups. This trial was registered at as NCT00069797. PMID:20357040

Ueshima, Hirotsugu; Curb, J David; Shin, Chol; Evans, Rhobert W; El-Saed, Aiman; Kadowaki, Takashi; Okamura, Tomonori; Nakata, Katsumi; Otake, Teruo; Miura, Katsuyuki; Abbott, Robert D; Sutton-Tyrrell, Kim; Edmundowicz, Daniel; Kuller, Lewis H; Sekikawa, Akira



Effect of drugs on high-density lipoprotein  

Microsoft Academic Search

The National Cholesterol Education Program Adult Treatment Panel III found evidence for raising high-density lipoprotein cholesterol (HDL-C) to reduce coronary artery disease (CAD) events supports use of HDL-C to help modify low-density lipoprotein cholesterol (LDL-C)?lowering goals, but not to establish new HDL-C?focused treatment recommendations. However, the HDL-C?raising clinical trials provide important lessons to help guide clinical management of dyslipidemic patients.

James M. McKenney



Structures of Discoidal High Density Lipoproteins  

PubMed Central

Conversion of discoidal phospholipid (PL)-rich high density lipoprotein (HDL) to spheroidal cholesteryl ester-rich HDL is a central step in reverse cholesterol transport. A detailed understanding of this process and the atheroprotective role of apolipoprotein A-I (apoA-I) requires knowledge of the structure and dynamics of these various particles. This study, combining computation with experimentation, illuminates structural features of apoA-I allowing it to incorporate varying amounts of PL. Molecular dynamics simulated annealing of PL-rich HDL models containing unesterified cholesterol results in double belt structures with the same general saddle-shaped conformation of both our previous molecular dynamics simulations at 310 K and the x-ray structure of lipid-free apoA-I. Conversion from a discoidal to a saddle-shaped particle involves loss of helicity and formation of loops in opposing antiparallel parts of the double belt. During surface expansion caused by the temperature-jump step, the curved palmitoyloleoylphosphatidylcholine bilayer surfaces approach planarity. Relaxation back into saddle-shaped structures after cool down and equilibration further supports the saddle-shaped particle model. Our kinetic analyses of reconstituted particles demonstrate that PL-rich particles exist in discrete sizes corresponding to local energetic minima. Agreement of experimental and computational determinations of particle size/shape and apoA-I helicity provide additional support for the saddle-shaped particle model. Truncation experiments combined with simulations suggest that the N-terminal proline-rich domain of apoA-I influences the stability of PL-rich HDL particles. We propose that apoA-I incorporates increasing PL in the form of minimal surface bilayers through the incremental unwinding of an initially twisted saddle-shaped apoA-I double belt structure. PMID:19948731

Gu, Feifei; Jones, Martin K.; Chen, Jianguo; Patterson, James C.; Catte, Andrea; Jerome, W. Gray; Li, Ling; Segrest, Jere P.



Scavenger Receptor Class B Type I Protein as an Independent Predictor of High-Density Lipoprotein  

E-print Network

is associated with elevated high-density lipoprotein (HDL)-cholesterol (HDL-C) levels. Objective: Our objective high-density lipoprotein (HDL)- cholesterol (HDL-C) levels and cardiovascular disease (1­3). Among lipoprotein; HDL-C, high-density lipoprotein-cholesterol; HT, hormone therapy; LCAT, lecithin-cholesterol

Terasaki, Mark


Effects of lipid-lowering drugs on intermediate-density lipoprotein in uremic patients  

Microsoft Academic Search

Effects of lipid-lowering drugs on intermediate-density lipoprotein in uremic patients.BackgroundPatients with chronic renal failure often have alterations in lipoprotein profile including elevated very-low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL), and reduced high density lipoprotein (HDL) levels. Among these changes, raised IDL has been shown as an independent risk factor for atherosclerosis in hemodialysis patients. There are a limited

Yoshiki Nishizawa; Tetsuo Shoji; Tsutomu Tabata; Takashi Inoue; Hirotoshi Morii



RESEARCH Open Access High-density lipoprotein proteome dynamics in  

E-print Network

RESEARCH Open Access High-density lipoprotein proteome dynamics in human endotoxemia Johannes HM in the HDL proteome have implications for the multiple functions of HDL. Here, SELDI-TOF mass spectrometry in the HDL proteome. Results: Plasma drawn at 7 time-points over a 24 hour time period after LPS challenge

Liège, Université de


High density lipoproteins (HDLs) and atherosclerosis; the unanswered questions  

Microsoft Academic Search

The concentration of high density lipoprotein-cholesterol (HDL-C) has been found consistently to be a powerful negative predictor of premature coronary heart disease (CHD) in human prospective population studies. There is also circumstantial evidence from human intervention studies and direct evidence from animal intervention studies that HDLs protect against the development of atherosclerosis. HDLs have several documented functions, although the precise

Philip Barter; John Kastelein; Alistair Nunn; Richard Hobbs



Low Density Lipoprotein Undergoes Oxidative Modification in vivo  

Microsoft Academic Search

It has been proposed that low density lipoprotein (LDL) must undergo oxidative modification before it can give rise to foam cells, the key component of the fatty streak lesion of atherosclerosis. Oxidation of LDL probably generates a broad spectrum of conjugates between fragments of oxidized fatty acids and apolipoprotein B. We now present three mutually supportive lines of evidence for

Wulf Palinski; Michael E. Rosenfeld; Seppo Yla-Herttuala; Geoff C. Gurtner; Steve S. Socher; Susan W. Butler; Sampath Parthasarathy; Thomas E. Carew; Daniel Steinberg; Joseph L. Witztum



Focus on high-density lipoproteins in reducing cardiovascular risk  

Microsoft Academic Search

Low high-density lipoprotein (HDL) cholesterol is associated with increased risk of coronary heart disease (CHD). Ongoing investigation into the mechanisms whereby HDL cholesterol might provide protection from atherosclerosis and clinical disease has resulted in improved understanding of the role of HDL in removal of cholesterol from the arterial wall and has suggested a number of strategies for augmenting the beneficial

H. Bryan Brewer



Pathophysiology and management of low high-density lipoprotein cholesterol  

Microsoft Academic Search

Low levels of high-density lipoprotein (HDL) cholesterol are associated with an increased risk of coronary artery disease events. Data in animals indicate that increasing HDL cholesterol levels decreases progression of atherosclerosis. Some clinical trials suggest a benefit from increasing HDL cholesterol levels, but additional data in humans are needed. Nevertheless, in patients with, or at high risk for, coronary artery

Daniel J Rader



Oxygen-Mediated Heterogeneity of Apo-Low-Density Lipoprotein  

Microsoft Academic Search

Mild oxidation of human serum low-density lipoprotein (LDL) converts the apoprotein from a nearly homogeneous component of high apparent molecular weight to a mixture of apparently lower molecular weight polypeptide components, as characterized by sodium dodecyl sulfate\\/ polyacrylamide gel electrophoresis. This protein alteration, which correlates temporally with increases in the formation of lipid oxidation products and in the fluorescence of

Joseph Schuh; Gordon F. Fairclough; Rudy H. Haschemeyer



Introduction Oxidation of low-density lipoproteins (LDL) plays an  

E-print Network

Introduction Oxidation of low-density lipoproteins (LDL) plays an important role in atherogenesis. Oxidized LDL (OxLDL) (and certain chemically modified LDL) have the ability to bind to scavenger receptorsLDL are present in plasma and lesions of humans and animals (1, 8­10), and small amounts of minimally oxidized LDL

Dennis, Edward A.


High-density lipoproteins: Physiopathological aspects and clinical significance  

SciTech Connect

This book contains 14 papers. Some of the titles are: HDL System: A Short Review of Structure and Metabolism; Human Apolipoprtein Genes: Organization and Expression; Binding Sites for HDL and HDL Catabolism; Clinical Significance of HDL: and Solubilization of Cholesterol by High-Density Lipoproteins.

Catapano, A.L.; Salvioli, G.; Vergani, C.



Recycling of vitamin E in human low density lipoproteins  

Microsoft Academic Search

Oxidative modification of low density lipoproteins (LDL) and their unrestricted scavenger receptordependent uptake is believed to account for cholesterol deposition in macrophagederived foam cells. It has been suggested that vitamin E that is transported by LDL plays a critical role in protecting against LDL oxidation. We hypothesize that the maintenance of sufficiently high vitamin E concentrations in LDL can be

Elena A. Serbinova; Trudy Forte; Giorgio Scita; Lester Packer


High density lipoprotein subfractions during semistarvation in obese women.  


The influence of a very low caloric diet (VLCD) on high density lipoproteins (HDL) is controversial. This study was designed to evaluate the influence of a VLCD on lipids and lipoproteins, especially on HDL subfractions (HDL2, HDL3) in obese women. After a 4-day period of isocaloric standard diet, 30 women at least 50% above ideal body weight were switched for 15 days on a protein-sparing modified diet providing 1.57 MJ per day. Mean body weight reduction was 5.6 +/- 0.7 kg. After the VLCD, total, very low density lipoproteins (VLDL), low density lipoproteins (LDL) and HDL cholesterol significantly decreased in all the subjects (p less than 0.01). Both HDL subfractions were depressed after the VLCD (p less than 0.01) but the reduction occurred predominantly in the HDL2 subfraction, thus inducing a decrease in the HDL2 to HDL3 cholesterol ratio (p less than 0.01). The VLCD was associated with a slight but not significant increase in the LDL to HDL cholesterol ratio. This increase was due mostly to the rise in the LDL to HDL2 cholesterol ratio (p less than 0.01). Further studies are needed to evaluate the long-term changes of HDL subfractions during weight-reducing regimens. PMID:3933405

Bosello, O; Cominacini, L; Zocca, I; Garbin, U; Davoli, A; Ferrari, F



Low-density lipoprotein and oxidised low-density lipoprotein: Their role in the development of atherosclerosis  

Microsoft Academic Search

Oxidation of low-density lipoprotein (LDL) may be implicated in the development of atherosclerotic disease. Oxidised LDL is taken up more readily by monocyte-derived macrophages than LDL. Antibodies to oxidised LDL are found in atherosclerotic lesions. Increased risk of ischaemic heart disease is associated with a preponderance of small dense LDL particles, which are more susceptible to oxidation. Proatherogenic alterations in

C. A. Hamilton



Effect of ethanol on low density lipoprotein and platelet composition  

Microsoft Academic Search

The present study was designed to investigate the effect of ethanol (EtOH) dose on low density lipoprotein (LDL) and platelet\\u000a composition. Male squirrel monkeys were divided into three groups designated Control, Low, and High EtOH, and fed isocaloric\\u000a liquid diets containing 0%, 12%, and 24% of calories as EtOH, respectively. After four months of treatment, monkeys fed the\\u000a 12% alcohol

Jerome L. Hojnacki; Joanne E. Cluette-Brown; Randall N. Deschenes; John J. Mulligan; Thaddeus V. Osmolski; Nicholas J. Rencricca; Joseph J. Barboriak; Joseph A. Jakubowski



Low-density lipoprotein profile changes during the neonatal period  

Microsoft Academic Search

Objective:To investigate natural change of low-density lipoprotein (LDL) profile during the neonatal period and the impact of gestational age and birth weight on those changes.Study Design:We measured lipid composition in LDL fraction, LDL particle size and apolipoprotein B (apoB) concentration at birth, 5 days of age and 1 month of age in 63 healthy neonates that had 37 to 41-week

H Fujita; T Okada; I Inami; M Makimoto; S Hosono; M Minato; S Takahashi; H Mugishima; T Yamamoto



Differential diagnosis of familial high density lipoprotein deficiency syndromes  

Microsoft Academic Search

Monogenic high density lipoprotein (HDL) deficiency, because of defects in the genes of apolipoprotein A-I (apoA-I), adenosine triphosphate binding cassette transporter A1 (ABCA1) or lecithin:cholesterol acyltransferase (LCAT), can be assumed in patients with HDL cholesterol levels below the fifth percentile within a given population. As in a first step underlying diseases should be excluded. Patients with a virtual absence of

Arnold von Eckardstein



21 CFR 866.5600 - Low-density lipoprotein immunological test system.  

...lipoprotein in serum and other body fluids. Measurement of low-density lipoprotein in serum may aid in the diagnosis of disorders of lipid (fat) metabolism and help to identify young persons at risk from cardiovascular diseases. (b) Classification....



21 CFR 866.5600 - Low-density lipoprotein immunological test system.  

Code of Federal Regulations, 2012 CFR

...lipoprotein in serum and other body fluids. Measurement of low-density lipoprotein in serum may aid in the diagnosis of disorders of lipid (fat) metabolism and help to identify young persons at risk from cardiovascular diseases. (b) Classification....



21 CFR 866.5600 - Low-density lipoprotein immunological test system.  

Code of Federal Regulations, 2013 CFR

...lipoprotein in serum and other body fluids. Measurement of low-density lipoprotein in serum may aid in the diagnosis of disorders of lipid (fat) metabolism and help to identify young persons at risk from cardiovascular diseases. (b) Classification....



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

SciTech Connect

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

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



Adenoviral expression of human lecithin-cholesterol acyltransferase in nonhuman primates leads to an antiatherogenic lipoprotein phenotype by increasing high-density lipoprotein and lowering low-density lipoprotein  

Microsoft Academic Search

Lecithin-cholesterol acyltransferase (LCAT), a key enzyme in high-density lipoprotein (HDL) metabolism, has been proposed to have atheroprotective properties by promoting reverse cholesterol transport. Overexpression of LCAT in various animal models, however, has led to conflicting results on its overall effect on lipoproteins and atherosclerosis. In this study, the effect of overexpression of LCAT in nonhuman primates on lipoprotein metabolism is

Marcelo J. A. Amar; Robert D. Shamburek; Boris Vaisman; Catherine L. Knapper; Bernhard Foger; Robert F. Hoyt Jr; Silvia Santamarina-Fojo; Hollis B. Brewer Jr; Alan T. Remaley



Mendelian disorders of high-density lipoprotein metabolism.  


High-density lipoproteins (HDLs) are a highly heterogeneous and dynamic group of the smallest and densest lipoproteins present in the circulation. This review provides the current molecular insight into HDL metabolism led by articles describing mutations in genes that have a large affect on HDL cholesterol levels through their roles in HDL and triglyceride metabolism. Using this information from both human and animal studies, it is discussed how HDL is produced, remodeled in the circulation, affected by factors that control the metabolism of triglyceride-rich lipoproteins, how it helps maintain cellular cholesterol homeostasis, and, finally, how it is catabolized. It can be concluded that HDL cholesterol as a trait is genetically heterogeneous, with as many as 40 genes involved. In most cases, only heterozygotes of gene variants are known, and HDL cholesterol as a trait is inherited in an autosomal-dominant manner. Only 3 Mendelian disorders of HDL metabolism are currently known, which are inherited in an autosomal-recessive mode. PMID:24385507

Oldoni, Federico; Sinke, Richard J; Kuivenhoven, Jan Albert



Low density lipoprotein cytotoxicity induced by free radical peroxidation of lipid  

Microsoft Academic Search

Low density lipoprotein (LDL) has been reported to be injurious or toxic to cells in vitro. This injurious effect is, in some instances, due to oxidation of the lipid moiety of the lipoprotein. The objectives of this study were to determine if the oxidation rendering the lipoprotein toxic to human skin fibroblasts occurred by free radical mechanisms, and if so,

Diane W. Morel; James R. Hessler; Guy M. Chisolm


A short-run new analytical ultracentrifugal micromethod for determining low-density lipoprotein sub-fractions using Schlieren refractometry.  


We have developed a new analytical ultracentrifugal micromethod for the determination of serum low-density lipoprotein (LDL) subclasses directly from ultracentrifugal Schlieren scans. We have used special software for the analysis of this type of single-spin density-gradient ultracentrifugation. The flotation of LDL patterns was obtained by underlayering a physiological salt solution with serum or isolated lipoprotein fractions raised to a density of 1.3 g/mL in the spinning ultracentrifugation capillary band-forming cell. The repeated analysis of Schlieren curves of the same sample from 10 to 100 microL in the 60-100 min full-speed interval time resulted in quite reproducible results. We obtained quantitative results by measuring the Schlieren areas between the sample curves and the reference baseline curve by using computerised numerical and graphic techniques. The decomposition of the integrated curve was carried out using a nonlinear regression program followed by deconvolution algorithm analysis in order to determine the parameters of the composing Gaussian subclasses. The LDL particle concentrations were calculated from the area under the integral of the Gaussian curve using a calibration data constant. The flotation range of the LDL Schlieren curves in the cell was identified with serum from which LDL had been removed by means of precipitation reagents and with centrifugation of isolated LDL aliquots. With this technique, we measured the concentration of LDL and analysed its polydispersity without the need for preceding sequential isolation of the LDL. On the basis of the Schlieren curves, the LDL samples were either physically paucidisperse, having a symmetrical peak within a narrow density range, or were polydisperse, showing an asymmetrical pattern distributed over a broader density region. The described method proved to be useful for a clear and immediate visual presentation of the concentration values of the LDL and for the identification of the heterogeneity of LDL variants without the need for the preparative isolation of that density class. PMID:11288837

Bozóky, Z; Fülöp, L; Köhidai, L



Low Density Lipoprotein Receptor-Related Protein 1 Dependent Endosomal Trapping and Recycling of Apolipoprotein E  

Microsoft Academic Search

BackgroundLipoprotein receptors from the low density lipoprotein (LDL) receptor family are multifunctional membrane proteins which can efficiently mediate endocytosis and thereby facilitate lipoprotein clearance from the plasma. The biggest member of this family, the LDL receptor-related protein 1 (LRP1), facilitates the hepatic uptake of triglyceride-rich lipoproteins (TRL) via interaction with apolipoprotein E (apoE). In contrast to the classical LDL degradation

Alexander Laatsch; Malamatenia Panteli; Marijke Sornsakrin; Britta Hoffzimmer; Thomas Grewal; Joerg Heeren



High-Density Lipoprotein Therapy: Is There Hope?  

Microsoft Academic Search

Opinion statement  The treatment of lipid abnormalities generally has focused on low-density lipoprotein cholesterol (LDL-C) reduction based\\u000a on extensive clinical trials and the National Cholesterol Education Program Adult Treatment Panel III guidelines. Unfortunately,\\u000a it has become increasingly clear that a significant percentage of patients continue to have cardiovascular events despite\\u000a being on LDL-C–lowering medications and having LDL-C levels below 100 mg\\/dL. Numerous

Kunal N. Bhatt; Bryan J. Wells; Laurence S. Sperling; Jefferson T. Baer



Very-Low-Density Lipoprotein-Induced Triglyceride Accumulation in Human Mesangial Cells Is Mainly Mediated by Lipoprotein Lipase  

Microsoft Academic Search

Background: Very-low-density lipoprotein (VLDL) in vitro can induce foam cell formation in human mesangial cells. Lipoprotein lipase (LPL) expressed in the arterial wall plays a key role in atherogenesis by actions of enzymolysis and ‘molecular bridge’, and, thereby, leads to the formation of lipid-loaded foam cells. It is known that LPL is expressed by glomerular mesangial cells. This study was

Jing Li; Hang Li; Yu-bing Wen; Xue-wang Li



Lipoprotein lipase binds to low density lipoprotein receptors and induces receptor-mediated catabolism of very low density lipoproteins in vitro.  


Lipoprotein lipase (LPL), the major enzyme responsible for the hydrolysis of plasma triglycerides, promotes binding and catabolism of triglyceride-rich lipoproteins by various cultured cells. Recent studies demonstrate that LPL binds to three members of the low density lipoprotein (LDL) receptor family, including the LDL receptor-related protein (LRP), GP330/LRP-2, and very low density lipoprotein (VLDL) receptors and induces receptor-mediated lipoprotein catabolism. We show here that LDL receptors also bind LPL and mediate LPL-dependent catabolism of large VLDL with Sf 100-400. Up-regulation of LDL receptors by lovastatin treatment of normal human foreskin fibroblasts (FSF cells) resulted in an increase in LPL-induced VLDL binding and catabolism to a level that was 10-15-fold greater than in LDL receptor-negative fibroblasts, despite similar LRP activity in both cell lines. This indicates that the contribution of LRP to LPL-dependent degradation of VLDL is small when LDL receptors are maximally up-regulated. Furthermore studies in LRP-deficient murine embryonic fibroblasts showed that the level of LPL-dependent degradation of VLDL was similar to that in normal murine embryonic fibroblasts. LPL also promoted the internalization of protein-free triglyceride emulsions; lovastatin-treatment resulted in 2-fold higher uptake in FSF cells, indicating that LPL itself could bind to LDL receptors. However, the lower induction of emulsion catabolism as compared with native VLDL suggests that LPL-induced catabolism via LDL receptors is only partially dependent on receptor binding by LPL and instead is primarily due to activation of apolipoproteins such as apoE. A fusion protein between glutathione S-transferase and the catalytically inactive carboxyl-terminal domain of LPL (GST-LPLC) also induced binding and catabolism of VLDL. However GST-LPLC was not as active as native LPL, indicating that lipolysis is required for a maximal LPL effect. Mutations of critical tryptophan residues in GST-LPLC that abolished binding to VLDL converted the protein to an inhibitor of lipoprotein binding to LDL receptors. In solid-phase assays using immobilized receptors, LDL receptors bound to LPL in a dose-dependent manner. Both LPL and GST-LPLC promoted binding of VLDL to LDL receptor-coated wells. These results indicate that LPL binds to LDL receptors and suggest that the carboxyl-terminal domain of LPL contributes to this interaction. PMID:8663292

Medh, J D; Bowen, S L; Fry, G L; Ruben, S; Andracki, M; Inoue, I; Lalouel, J M; Strickland, D K; Chappell, D A



Rationale for Use of Non–High-Density Lipoprotein Cholesterol Rather Than Low-Density Lipoprotein Cholesterol as a Tool for Lipoprotein Cholesterol Screening and Assessment of Risk and Therapy  

Microsoft Academic Search

The plasma level of low-density lipoprotein (LDL) cholesterol is the “gold standard” for estimating the lipoprotein-related risk for complications of atherosclerotic vascular disease. LDL cholesterol concentrations are commonly estimated by the Friedewald formula that requires only the measurement (after overnight fasting) of plasma cholesterol and triglycerides along with high-density lipoprotein (HDL) cholesterol. This value, however, is not in fact a

Philip H Frost; Richard J Havel



A procedure for the determination of high-density lipoprotein choline-containing phospholipids.  


A procedure for the determination of serum high-density lipoprotein choline-containing phospholipids is described. The choline-containing phospholipids represent 91-97% of the total serum and high-density lipoprotein phospholipids, which have previously been determined in relation to liver disease, neoplastic disorders, diabetes mellitus and atherosclerosis. The enzymatic assay is quick, simple and precise. No interference was found from the precipitating agents used to isolate the high-density lipoprotein fraction. Several serum samples were assayed for high-density lipoprotein cholesterol and choline-containing phospholipids. From this preliminary data there would appear to be a correlation between these two lipid classes. PMID:7153717

McGowan, M W; Artiss, J D; Zak, B



Cholesterol transfer from normal and atherogenic low density lipoproteins to Mycoplasma membranes  

SciTech Connect

The purpose of this study was to determine whether the free cholesterol of hypercholesterolemic low density lipoprotein from cholesterol-fed nonhuman primates has a greater potential for surface transfer to cell membranes than does the free cholesterol of normal low density lipoprotein. The low density lipoproteins were isolated from normal and hypercholesterolemic rhesus and cynomolgus monkeys, incubated with membranes from Acholeplasma laidlawii, a mycoplasma species devoid of cholesterol in its membranes, and the mass transfer of free cholesterol determined by measuring membrane cholesterol content. Since these membranes neither synthesize nor esterify cholesterol, nor degrade the protein or cholesterol ester moieties of low density lipoprotein, they are an ideal model with which to study differences in the cholesterol transfer potential of low density lipoprotein independent of the uptake of the intact low density lipoprotein particle. These studies indicate that, even though there are marked differences in the cholesterol composition of normal and hypercholesterolemic low density lipoproteins, this does not result in a greater chemical potential for surface transfer of free cholesterol. Consequently, if a difference in the surface transfer of free cholesterol is responsible for the enhanced ability of hypercholesterolemic low density lipoprotein to promote cellular cholesterol accumulation and, perhaps, also atherosclerosis, it must be the result of differences in the interaction to the hypercholesterolemic low density lipoprotein with the more complicated mammalian cell membranes, rather than differences in the chemical potential for cholesterol transfer.

Mitschelen, J.J.; St. Clair, R.W.; Hester, S.H.



Beyond Low-Density Lipoprotein Cholesterol Respective Contributions of Non-High-Density Lipoprotein Cholesterol Levels, Triglycerides, and the Total Cholesterol\\/High-Density Lipoprotein Cholesterol Ratio to Coronary Heart Disease Risk in Apparently Healthy Men and Women  

Microsoft Academic Search

OBJECTIVES: This study was designed to test the hypothesis that at any low-density lipoprotein cholesterol (LDL-C) level, other lipid parameters such as non-high-density lipoprotein cholesterol (HDL-C) levels, triglyceride (TG) levels, and the total cholesterol (TC)\\/HDL-C are still associated with an increased coronary heart disease (CHD) risk. BACKGROUND: Although LDL-C is considered to be the primary target of lipid-lowering therapy, other

B. J. Arsenault; J. S. Rana; E. S. G. Stroes; J. P. Després; P. K. Shah; J. J. P. Kastelein; N. J. Wareham; S. M. Boekholdt; K. T. Khaw



Protein carbamylation renders high-density lipoprotein dysfunctional.  


Carbamylation of proteins through reactive cyanate has been demonstrated to predict an increased cardiovascular risk. Cyanate is formed in vivo by breakdown of urea and at sites of inflammation by the phagocyte protein myeloperoxidase. Because myeloperoxidase (MPO) associates with high-density lipoprotein (HDL) in human atherosclerotic intima, we examined in the present study whether cyanate specifically targets HDL. Mass spectrometry analysis revealed that protein carbamylation is a major posttranslational modification of HDL. The carbamyllysine content of lesion-derived HDL was more than 20-fold higher in comparison with 3-chlorotyrosine levels, a specific oxidation product of MPO. Notably, the carbamyllysine content of lesion-derived HDL was five- to eightfold higher when compared with lesion-derived low-density lipoprotein (LDL) or total lesion protein and increased with lesion severity. The carbamyllysine content of HDL, but not of LDL, correlated with levels of 3-chlorotyrosine, suggesting that MPO mediated carbamylation in the vessel wall. Remarkably, one carbamyllysine residue per HDL-associated apolipoprotein A-I was sufficient to induce cholesterol accumulation and lipid-droplet formation in macrophages through a pathway requiring the HDL-receptor scavenger receptor class B, type I. The present results raise the possibility that HDL carbamylation contributes to foam cell formation in atherosclerotic lesions. PMID:21235354

Holzer, Michael; Gauster, Martin; Pfeifer, Thomas; Wadsack, Christian; Fauler, Guenter; Stiegler, Philipp; Koefeler, Harald; Beubler, Eckhard; Schuligoi, Rufina; Heinemann, Akos; Marsche, Gunther



Isolation of serum chylomicrons prior to density gradient ultracentrifugation of other serum lipoprotein classes.  


A method for the removal of serum chylomicrons before density gradient ultracentrifugation of the other serum lipoproteins using an SW 41 swinging bucket rotor is presented. In a preliminary spin, the chylomicrons with an Sf greater than 400 X 10(-13) s float to the top of the gradient, whereas the other lipoproteins are retained in the infranatant fraction. After removal of the chylomicrons, the other serum lipoproteins are subsequently fractionated by isopycnic density gradient ultracentrifugation. Analysis of the separated lipoprotein fractions suggested that this procedure permits isolation of a chylomicron fraction consisting solely of chylomicrons but that the very low density lipoprotein fraction subsequently isolated also contains chylomicrons or chylomicron remnants with an Sf less than 400 X 10(-13) s, and that there is considerable overlap in flotation rate and particle size of very low density lipoproteins and chylomicrons. PMID:4083481

Terpstra, A H



Low Density Lipoprotein-Cholesterol/High Density Lipoprotein-Cholesterol Ratio Predicts Plaque Vulnerability in Patients With Stable Angina  

PubMed Central

Background and Objectives The relationship between lipid profile and coronary plaque tissue characteristics in patients with stable angina pectoris (SAP) is unclear. The aim of this study was to evaluate the relationship between tissue characteristics and lipid profile and predictors of unstable plaques (UPs) in patients with SAP by virtual histology intravascular ultrasonography (VH-IVUS). Subjects and Methods VH-IVUS was performed for target lesions in patients with SAP (61.7±9.2 years, 174 males, n=266) at the time of coronary angiography. UPs are characterized by thin-cap fibroatheroma, ruptured plaque, or remaining thrombus with VH-IVUS. Results The present study showed that 34 SAP patients had UPs (61.6±9.2 years, 24 males, 12.8%). The percentage of plaque area in the minimum luminal area in high low density lipoprotein-cholesterol (LDL-C)/high density lipoprotein-cholesterol (HDL-C) ratio patients was significantly higher than in low LDL-C/HDL-C ratio patients (72.7±9.5% vs. 69.9±9.3%, p=0.035). An LDL-C/HDL-C ratio >2.0 was an independent predictor for UPs in SAP patients (odds ratio 5.252, 95% confidence interval 1.132-24.372, p=0.034). Conclusion An elevated LDL-C/HDL-C ratio is a positive predictor for coronary plaque vulnerability in patients with SAP. PMID:22563337

Kim, Jeong Hun; Hong, Young Joon; Lee, Ki Hong; Kim, In Soo; Choi, Yun Ha; Lee, Min Goo; Park, Keun-Ho; Sim, Doo Sun; Kim, Ju Han; Ahn, Youngkeun; Cho, Jeong Gwan; Park, Jong Chun; Kang, Jung Chaee



Reconstitution of the trypanolytic factor from components of a subspecies of human high-density lipoproteins.  


Trypanosoma brucei brucei is non-infectious to man due to the sensitivity of these parasites to the lytic activity of normal human serum. Apolipoproteins (apo) have been purified, under non-denaturing conditions, from the subclass of human high-density lipoprotein (HDL), termed trypanosome lytic factor (TLF), which is responsible for the cytotoxicity of human serum to T. b. brucei. The TLF apolipoproteins were purified by anion exchange chromatography in the presence of the nonionic detergent octylglucoside and a reconstitution method was developed which allowed the role of the individual apolipoproteins and different lipids to be assessed. The results suggest that the TLF lipids do not have a direct role in lysis but are necessary for the correct assembly of the lytic HDL particle. Apo A-I, apo L-III and apo L-I contribute to lysis in reconstituted particles but individually they are not cytotoxic. Apo A-II was not required in the reconstituted TLF particle for trypanosome lysis. Formation of a lytic HDL particle required apo L-III suggesting its potential role as a toxin. Thermal inactivation of TLF activity correlated with the amount of denatured apo L-I, indicating that apo L-I was involved in lysis of T. b. brucei by native TLF. PMID:7723792

Tytler, E M; Moore, D R; Pierce, M A; Hager, K M; Esko, J D; Hajduk, S L



Association between low density lipoprotein and rheumatoid arthritis genetic factors with low density lipoprotein levels in rheumatoid arthritis and non-rheumatoid arthritis controls  

E-print Network

Objectives: While genetic determinants of low density lipoprotein (LDL) cholesterol levels are well characterised in the general population, they are understudied in rheumatoid arthritis (RA). Our objective was to determine ...

Liao, K. P.


Inhibition of Low Density Lipoprotein Synthesis by Dietary Omega3 Fatty Acids in Humans  

Microsoft Academic Search

Diets rich in omega-3 fatty acids derived from fish oils lower the plasma concentra- tions of low density lipoproteins (LDL) and very low density lipoproteins in humans. The present study was designed to examine the mechanism(s) by which diets en- riched in omega-3 fatty acids reduce plasma LDL cholesterol levels in normal sub- jects. Seven healthy volunteers with normal plasma

D. Roger Illingworth; William S. Harris; William E. Connor



Fitness, Heart Disease, and High-Density Lipoproteins: A Look at the Relationships.  

ERIC Educational Resources Information Center

The role of fitness in preventing coronary heart disease is explored. Research on high-density lipoprotein, which has been found to be one of the most critical determinants of risk, is reviewed. The relationship between fitness, high-density lipoprotein, and coronary heart disease is assessed, and clinical implications are spelled out. (MT)

McCunney, Robert J.



Knowledge-Driven Analysis Identifies a GeneGene Interaction Affecting High-Density Lipoprotein  

E-print Network

-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease Cholesterol Levels in Multi-Ethnic Populations Li Ma1 , Ariel Brautbar2 , Eric Boerwinkle3 , Charles F. Sing4 States of America Abstract Total cholesterol, low-density lipoprotein cholesterol, triglyceride, and high

Keinan, Alon


Identification of Scavenger Receptor SR-BI as a High Density Lipoprotein Receptor  

Microsoft Academic Search

High density lipoprotein (HDL) and low density lipoprotein (LDL) are cholesterol transport particles whose plasma concentrations are directly (LDL) and inversely (HDL) correlated with risk for atherosclerosis. LDL catabolism involves cellular uptake and degradation of the entire particle by a well-characterized receptor. HDL, in contrast, selectively delivers its cholesterol, but not protein, to cells by unknown receptors. Here it is

Susan Acton; Attilio Rigotti; Katherine T. Landschulz; Shangzhe Xu; Helen H. Hobbs; Monty Krieger



High-Density Lipoprotein and Prostate Cancer: An Overview  

PubMed Central

Prostate cancer is a common disease in modern, developed societies and has a high incidence and mortality. High-density lipoprotein cholesterol (HDL-C) has recently received much attention as a possible risk marker of prostate cancer development and prognosis. In the present article, we summarized findings from epidemiologic studies of the association between HDL-C and prostate cancer. Low HDL-C level was found to be a risk and prognostic factor of prostate cancer in several epidemiologic studies, although the overall linkage between HDL and prostate cancer has not been definitively established. The mechanisms for this association remain uncertain; however, limited data from experimental studies imply a possible role of HDL in the pathophysiology of prostate cancer. More epidemiologic research, in combination with experimental studies, is needed in this field. PMID:23985823

Kotani, Kazuhiko; Sekine, Yoshitaka; Ishikawa, Shizukiyo; Ikpot, Imoh Z.; Suzuki, Kazuhiro; Remaley, Alan T.



High density lipoprotein: it's not just about lipid transport anymore  

PubMed Central

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

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



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

SciTech Connect

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

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



The main lytic factor of Trypanosoma brucei brucei in normal human serum is not high density lipoprotein  

PubMed Central

Natural immunity of humans to the cattle pathogen Trypanosoma brucei brucei has been attributed to the presence in normal human serum (NHS) of lytic factors for the parasites. We and others have shown that NHS contains two trypanolytic factors (herein termed TLF1 and TLF2) that can be separated by gel filtration. TLF1 copurifies with a subclass of high density lipoprotein (HDL), whereas TLF2 has a much higher molecular weight and does not appear to be a lipoprotein. We find that the trypanolytic activity of purified TLF1 is totally inhibited by exogenous haptoglobin (Hp) at concentrations (0.1 mg/ml) lower than those present in NHS (0.2-2 mg/ml). In contrast, exogenous Hp (up to 2.5 mg/ml) has no effect on the lytic activity of either NHS or isolated TLF2. Hp-depleted sera from patients with intravascular hemolysis is severalfold more trypanolytic than NHS. These sera contain only TLF1, and their lytic activity is totally abolished upon the addition of Hp (0.1 mg/ml). When NHS containing different Hp allotypes is fractionated by gel filtration, TLF1 activity is either revealed or remains masked, depending on whether it coelutes with Hp. Masked TLF1 activity in the column fractions is revealed if Hp is removed by density gradient ultracentrifugation. We conclude that endogenous Hp inhibits TLF1 activity, and that TLF2 is the main trypanolytic factor in NHS. PMID:8642243



High Density Lipoprotein Level is Negatively Associated With the Increase of Oxidized Low Density Lipoprotein Lipids After a Fatty Meal.  


Recent reports show that a fatty meal can substantially increase the concentration of oxidized lipids in low density lipoprotein (LDL). Knowing the LDL-specific antioxidant effects of high density lipoprotein (HDL), we aimed to investigate whether HDL can modify the postprandial oxidative stress after a fatty meal. Subjects of the study (n = 71) consumed a test meal (a standard hamburger meal) rich in lipid peroxides, and blood samples were taken before, 120, 240, and 360 min after the meal. The study subjects were divided into four subgroups according to the pre-meal HDL cholesterol value (HDL subgroup 1, 0.66-0.91; subgroup 2, 0.93-1.13; subgroup 3, 1.16-1.35; subgroup 4, 1.40-2.65 mmol/L). The test meal induced a marked postprandial increase in the concentration of oxidized LDL lipids in all four subgroups. The pre-meal HDL level was associated with the extent of the postprandial rise in oxidized LDL lipids. From baseline to 6 h after the meal, the concentration of ox-LDL increased by 48, 31, 24, and 16 % in the HDL subgroup 1, 2, 3, and 4, respectively, and the increase was higher in subgroup 1 compared to subgroup 3 (p = 0.028) and subgroup 4 (p = 0.0081), respectively. The pre-meal HDL correlated with both the amount and the rate of increase of oxidized LDL lipids. Results of the present study show that HDL is associated with the postprandial appearance of lipid peroxides in LDL. It is therefore likely that the sequestration and transport of atherogenic lipid peroxides is another significant mechanism contributing to cardioprotection by HDL. PMID:25359080

Tiainen, Sanna; Ahotupa, Markku; Ylinen, Petteri; Vasankari, Tommi



A 90 minute soccer match decreases triglyceride and low density lipoprotein but not high-density lipoprotein and cholesterol levels  

PubMed Central

BACKGROUND: The association between the lipid profiles level and the incidence and severity of coronary heart disease (CHD) is very pronounced in epidemiological studies, and an inverse relation between physical fitness and the incidence of coronary heart disease has been observed in many studies. The aim of this study was to investigate the impact of a soccer match on lipid parameters of professional soccer players. METHODS: Twenty two professional soccer players participated in the study. Blood (10ml) for determination of lipid profiles was obtained at rest and immediately after a 90 minute soccer match. Lipid parameters were measured using Boehringer Mannheim kits and Clinilab and BioMerieux analyser. RESULTS: The results of this study showed that the triglyceride was significantly higher before the match than afterwards (159.09 ± 58.2 vs. 88.63 ± 34.1 mg/dl, p < 0.001), whereas the low-density lipoprotein (LDL) was lower before the match than after it (98.04 ± 28.9 vs. 112.31 ± 30.5 mg/dl). Moreover, there were no significant differences in cholesterol concentration (171.4 ± 30.28 mg/dl vs. 173.18 ± 32.75 mg/dl) and high-density lipoprotein (HDL) concentration (34.04 ± 5.58 mg/dl vs. 34.4 ± 4.6 mg/dl) between before and after the match. CONCLUSIONS: Although the soccer competitive match has no favourable acute effect on lipid profiles, the lower rate of LDL, cholesterol and triglyceride as well as the higher level of HDL in players suggest a beneficial effect of regular soccer training on arthrosclerosis and perhaps on CHD risk as well. PMID:21772906

Rahnama, Nader; Younesian, Ali; Mohammadion, Morteza; Bambaeichi, Effat



Proprotein convertases in high-density lipoprotein metabolism  

PubMed Central

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



Degradation of high density lipoprotein in cultured rat luteal cells  

SciTech Connect

In rat ovary luteal cells, degradation of high density lipoprotein (HDL) to tricholoracetic acid (TCA)-soluble products accounts for only a fraction of the HDL-derived cholesterol used for steroidogenesis. In this study the authors have investigated the fate of /sup 125/I)HDL bound to cultured luteal cells using pulse-chase technique. Luteal cell cultures were pulse labeled with (/sup 125/I)HDL/sub 3/ and reincubated in the absence of HDL. By 24 h about 50% of the initallay bound radioactivity was released into the medium, of which 60-65% could be precipitated with 10% TCA. Gel filtration of the chase incubation medium on 10% agarose showed that the amount of TCA-soluble radioactivity was nearly completely accounted for by a sharp peak in the low molecular weight region which was identified as 96% monoiodotyrosine by paper chromatography. The TCA-precipitable radioactivity was nearly completely accounted for by a sharp peak in the low molecular weight region which was identified as 96% monoiodotyrosine by paper chromatography. The TCA-precipitable radioactivity eluted over a wide range of molecular weights (15,000-80,000), and there was very little intact HDL present. Electrophoresis of the chase medium showed that component of the TCA-precipitable portion had mobility similar to apo AI. Lysosomal inhibitors of receptor-mediated endocytosis had no effect on the composition or quantity of radioactivity released during chase incubation. The results show that HDL/sub 3/ binding to luteal cells is followed by complete degradation of the lipoprotein, although the TCA-soluble part does not reflect the extent of degradation.

Rajan, V.P.; Menon, K.M.J.



Effects of atorvastatin 10 mg and fenofibrate 200 mg on the low-density lipoprotein profile in dyslipidemic patients: A 12-week, multicenter, randomized, open-label, parallel-group study  

Microsoft Academic Search

Background: Elevated plasma low-density lipoprotein cholesterol (LDL-C) concentrations are highly atherogenic, especially the small, dense LDL (sdLDL) species. Fenofibrate has been reported to shift the LDL profile by decreasing the sdLDL subfraction and increasing larger LDL subclasses. Atorvastatin, anantihyperlipidemic agent, has been reported to reduce plasma total cholesterol (TC) and triglyceride (TG) concentrations and thus could modify the LDL profile.Objective:

Jean-Claude Ansquer; Christophe Corda; Karine Le Malicot; Valerie Jessent



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

PubMed Central

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

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



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


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

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



Bidirectional flux of cholesterol between cells and lipoproteins. Effects of phospholipid depletion of high density lipoprotein  

SciTech Connect

The bidirectional surface transfer of free cholesterol (FC) between Fu5AH rat hepatoma cells and human high density lipoprotein (HDL) was studied. Cells and HDL were prelabeled with (4-/sup 14/C)FC and (7-/sup 3/H)FC, respectively. Influx and efflux of FC were measured simultaneously from the appearance of /sup 3/H counts in cells and /sup 14/C counts in medium. Results were analyzed by a computerized procedure which fitted sets of kinetic data to a model assuming that cell and HDL FC populations each formed a single homogeneous pool and that together the pools formed a closed system. This analysis yielded values for the first-order rate constants of FC influx and efflux (ki and ke), from which influx and efflux of FC mass (Fi and Fe) could be calculated. With normal HDL, the uptake and release of FC tracers conformed well to the above-described model; Fi and Fe were approximately equal, suggesting an exchange of FC between cells and HDL. HDL was depleted of phospholipid (PL) by treatment with either phospholipase A2 or heparin-releasable rat hepatic lipase, followed by incubation with bovine serum albumin. PL depletion of HDL had little or no effect on ki, but reduced ke, indicating that PL-deficient HDL is a relatively poor acceptor of cell cholesterol. The reduction in ke resulted in initial Fi greater than Fe and, thus, in net uptake of FC by the cells. This result explained previous results demonstrating net uptake of FC from PL-depleted HDL. In the presence of an inhibitor of acyl coenzyme A:cholesterol acyltransferase, the steady state distribution of FC mass between cells and HDL was accurately predicted by the ratio of rate constants for FC flux. This result provided additional validation for describing FC flux in terms of first-order rate constants and homogeneous cell and HDL FC pools.

Johnson, W.J.; Bamberger, M.J.; Latta, R.A.; Rapp, P.E.; Phillips, M.C.; Rothblat, G.H.



High-density lipoprotein, beta cells, and diabetes .  


High-density lipoproteins (HDLs) exert a series of potentially beneficial effects on many cell types including anti-atherogenic actions on the endothelium and macrophage foam cells. HDLs may also exert anti-diabetogenic functions on the beta cells of the endocrine pancreas, notably by potently inhibiting stress-induced cell death and enhancing glucose-stimulated insulin secretion. HDLs have also been found to stimulate insulin-dependent and insulin-independent glucose uptake into skeletal muscle, adipose tissue, and liver. These experimental findings and the inverse association of HDL-cholesterol levels with the risk of diabetes development have generated the notion that appropriate HDL levels and functionality must be maintained in humans to diminish the risks of developing diabetes. In this article, we review our knowledge on the beneficial effects of HDLs in pancreatic beta cells and how these effects are mediated. We discuss the capacity of HDLs to modulate endoplasmic reticulum stress and how this affects beta-cell survival. We also point out the gaps in our understanding on the signalling properties of HDLs in beta cells. Hopefully, this review will foster the interest of scientists in working on beta cells and diabetes to better define the cellular pathways activated by HDLs in beta cells. Such knowledge will be of importance to design therapeutic tools to preserve the proper functioning of the insulin-secreting cells in our body. PMID:24903496

von Eckardstein, Arnold; Widmann, Christian



Tiliroside and gnaphaliin inhibit human low density lipoprotein oxidation.  


Two flavonoids, gnaphaliin and tiliroside, isolated from Helichrysum italicum, were studied in vitro for their capacity to inhibit Cu(2+)-induced human low density lipoprotein (LDL) and diluted plasma oxidation. LDL oxidation was monitored by conjugated diene, thiobarbituric acid-reactive substances (TBARS) formation and electrophoretic mobility on agarose gel. Gnaphaliin and tiliroside increased the lag-phase for diene conjugate production in a dose-dependent manner. The reduction of TBARS production confirmed the antioxidant activity of gnaphaliin and tiliroside with 50% inhibitory concentration (IC(50)) values of 8.0+/-3.9 microM and 7.0+/-2.6 microM respectively. Furthermore, the flavonoids negated the Cu(2+)-induced increase in electrophoretic mobility of LDL. Antioxidant activity of gnaphaliin and tiliroside was significantly different when diluted plasma was oxidised by adding 1 mM CuSO(4). Although both flavonoids again reduced the TBARS production, tiliroside showed higher activity than gnaphaliin (IC(50)=10.6+/-2.5 microM vs. IC(50)>50 microM). In conclusion, tiliroside and gnaphaliin are antioxidants against in vitro Cu(2+)-induced LDL oxidation in the same order of magnitude compared to that of the reference drug, probucol. PMID:17084992

Schinella, Guillermo R; Tournier, Horacio A; Máñez, Salvador; de Buschiazzo, Perla M; Del Carmen Recio, María; Ríos, José Luis



High Density Lipoprotein: A Therapeutic Target in Type 2 Diabetes  

PubMed Central

High density lipoproteins (HDLs) have a number of properties that have the potential to inhibit the development of atherosclerosis and thus reduce the risk of having a cardiovascular event. These protective effects of HDLs may be reduced in patients with type 2 diabetes, a condition in which the concentration of HDL cholesterol is frequently low. In addition to their potential cardioprotective properties, HDLs also increase the uptake of glucose by skeletal muscle and stimulate the synthesis and secretion of insulin from pancreatic ? cells and may thus have a beneficial effect on glycemic control. This raises the possibility that a low HDL concentration in type 2 diabetes may contribute to a worsening of diabetic control. Thus, there is a double case for targeting HDLs in patients with type 2 diabetes: to reduce cardiovascular risk and also to improve glycemic control. Approaches to raising HDL levels include lifestyle factors such as weight reduction, increased physical activity and stopping smoking. There is an ongoing search for HDL-raising drugs as agents to use in patients with type 2 diabetes in whom the HDL level remains low despite lifestyle interventions. PMID:24396675



Ethanol enhances de novo synthesis of high density lipoprotein cholesterol  

SciTech Connect

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

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



High-density lipoprotein endocytosis in endothelial cells  

PubMed Central

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

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



Phospholipid transfer protein gene knock-out mice have low high density lipoprotein levels, due to hypercatabolism, and accumulate apoA-IV-rich lamellar lipoproteins  

Microsoft Academic Search

Phospholipid transfer protein gene knock-out ( Pltp KO) mice have defective transfer of very low density lipoprotein (VLDL) phospholipids into high density lipo- protein (HDL) and markedly decreased HDL levels ( Jiang et al. 1999. J. Clin. Invest. 103: 907-914). These animals also accumulated VLDL- and LDL-sized lipoproteins on a high saturated fat diet. The goals of this study were

Shucun Qin; Koichi Kawano; Can Bruce; Min Lin; Charles Bisgaier; Alan R. Tall; Xian-cheng Jiang


Plasma lipoprotein concentration as an indicator of fatness in broilers: Development and use of a simple assay for plasma very low density lipoproteins  

Microsoft Academic Search

1. A turbidimetric assay for plasma very low density lipoproteins (VLDL) was developed, based on their selective precipitation with heparin and Mg.2. Measurements of plasma VLDL concentration using the turbidimetric method showed a correlation of 0–98 with plasma VLDL plus low density lipoprotein triglyceride concentration estimated chemically.3. Correlations between plasma VLDL concentration measured turbidimetrically and body fat content were similar

H. D. Griffin; C. C. Whitehead



Inhibition of lung carcinoma cell growth by high density lipoprotein-associated alpha-tocopheryl-succinate.  


Alpha-tocopheryl-succinate (alphaTS) is a synthetic, anti-neoplastic derivative of alpha-tocopherol. Here we studied the effects of free and high-density lipoprotein subclass 3 (HDL3)-associated alphaTS on the growth of human (A549) and mouse Lewis (LL2) lung carcinoma cells. Both free and HDL3-associated alphaTS inhibited A549 growth in a time- and concentration-dependent manner. Treatment of A549 cells with alphaTS-enriched HDL3 led to DNA fragmentation and a time-dependent decrease in immunoreactivity of poly(ADP-ribose)polymerase. Uptake experiments revealed a high capacity for selective alphaTS uptake in excess of holoparticle endocytosis. Overexpression of scavenger receptor class B, type I (SR-BI), the prime receptor mediating selective lipid uptake, in A549 cells resulted in significantly increased selective alphaTS uptake, a finding associated with complete cellular growth arrest. The present in vitro findings were verified in an in vivo model: tumor inoculation in C57BL6 was performed with either wild-type, beta-galactosidase- or SR-BI-overexpressing LL2 cells. After tumor inoculation, the animals received six consecutive intravenous injections of alphaTS. This experimental setup resulted in significantly reduced tumor burden in animals that were inoculated with SR-BI-overexpressing LL2 cells but not in animals inoculated with wild-type or beta-galactocidase-transfected cells. Based on our in vitro and in vivo findings, we propose that SR-BI could provide a novel route for HDL3-mediated drug delivery of anti-neoplastic drugs. PMID:15197475

Hrzenjak, A; Reicher, H; Wintersperger, A; Steinecker-Frohnwieser, B; Sedlmayr, P; Schmidt, H; Nakamura, T; Malle, E; Sattler, W



Peroxisome Proliferator-activated Receptor / Regulates Very Low Density Lipoprotein Production and Catabolism in  

E-print Network

Peroxisome Proliferator-activated Receptor / Regulates Very Low Density Lipoprotein Production, Pennsylvania 16802 The results of recent studies using selective agonists for peroxisome proliferator in the improvement of serum lipids in the setting of metabolic syndrome. The peroxisome proliferator

Omiecinski, Curtis


High density lipoprotein isolation and characterization to obtain high purity HDL samples for immunological assays.  

E-print Network

??Seit der Erkenntnis, dass niedrige Blutwerte an HDL-C (high density lipoprotein-cholesterol) ein erhöhtes Risiko für kardiovaskuläre Erkrankungen darstellen, ist HDL in den Fokus der Forschung… (more)

Michlits, Georg



A comprehensive evaluation of the heparin-manganese precipitation procedure for estimating high density lipoprotein cholesterol  

Microsoft Academic Search

The accurate quantitation of high density lipo- proteins has recently assumed greater importance in view of studies suggesting their negative correlation with coronary heart disease. High density lipoproteins may be estimated by measuring cholesterol in the plasma frac- tion of d > 1.063 g\\/ml. A more practical approach is the specific precipitation of apolipoprotein B (apoB)-contain- ing lipoproteins by sulfated

G. Russell Warnick; John J. Albers


Raising high-density lipoprotein cholesterol with niacin and fibrates: a comparative review  

Microsoft Academic Search

A growing number of trials that used fibrates and niacin alone or in combination with other lipid-altering agents have shown that both these drugs are effective for reducing total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides, and for increasing high-density lipoprotein cholesterol (HDL-C) levels. These lipid changes are associated with a reduction in events such as fatal and nonfatal myocardial

Dennis L Sprecher



A genetic determinant of the phenotypic variance of the molecular weight of low density lipoprotein.  


The molecular weight of monodisperse human plasma low densitylipoprotein has been measured in 69 individuals and found to vary over the range of 2.4 to 3.9 X 10-6. By contrast, the molecular weight of low density lipoprotein measured on two separate occasions for specific individuals shows a mean difference of 0.07 X 10-6 and a standard deviation of 0.08 X 10-6; hence low density lipoprotein differing in molecular weight by greater than 0.2 X 10-6 may be considered different macomolecules. The distribution of the molecular weight of low density lipoprotein does not differ as a function of age or sex. Hyperlipemic subjects having monodisperse low density lipoprotein show similar molecular weight distribution to normal subjects, as do subjects with premature coronary artery disease. Family studies reveal a correlation coefficient of 0.82 between average molecular weights of parents and offspring, with significance at 0.01. In order to assess the influence of environment on molecular weight of low density lipoprotein, the correlation coefficient between the fathers' and mothers' low density lipoprotein was measured and no statistically significant correlation was found. These data are interpreted as strong evidence for a genetic determination of molecular weight of low density lipoprotein. A study of individuals in five families yields molecular weight data consistent with a single gene locus genetic mode of inheritance without dominance. The regression coefficient of the mean low denisty lipoprotein parental molecular weight on the offspring molecular weight is 0.30. If the variability of molecular weight is considered as an expression of phenotypic variance, then the regression analysis identified 30% of this phenotypic variance as arising from additive gene action presumably at a single locus. Segregation in the family data is consistent. Since the differences in molecular weight of low density lipoprotein arise from differences in the amount of lipid bound to the apoprotein, it is likely that an additional portion of the phenotypic variance of the molecular weight results from individual variations in the metabolism of low density lipoprotein, which yield differences in lipid content. The individual variation in molecular weight is only approximately 5%; hence those metabolic sequences that influence molecular weight of low density lipoproteins must be precisely controlled. PMID:166386

Fisher, W R; Hammond, M G; Mengel, M C; Warmke, G L



High-density lipoprotein and atherosclerosis: Roles of lipid transporters.  


Various previous studies have found a negative correlation between the risk of cardiovascular events and serum high-density lipoprotein (HDL) cholesterol levels. The reverse cholesterol transport, a pathway of cholesterol from peripheral tissue to liver which has several potent antiatherogenic properties. For instance, the particles of HDL mediate to transport cholesterol from cells in arterial tissues, particularly from atherosclerotic plaques, to the liver. Both ATP-binding cassette transporters (ABC) A1 and ABCG1 are membrane cholesterol transporters and have been implicated in mediating cholesterol effluxes from cells in the presence of HDL and apolipoprotein A-I, a major protein constituent of HDL. Previous studies demonstrated that ABCA1 and ABCG1 or the interaction between ABCA1 and ABCG1 exerted antiatherosclerotic effects. As a therapeutic approach for increasing HDL cholesterol levels, much focus has been placed on increasing HDL cholesterol levels as well as enhancing HDL biochemical functions. HDL therapies that use injections of reconstituted HDL, apoA-I mimetics, or full-length apoA-I have shown dramatic effectiveness. In particular, a novel apoA-I mimetic peptide, Fukuoka University ApoA-I Mimetic Peptide, effectively removes cholesterol via specific ABCA1 and other transporters, such as ABCG1, and has an antiatherosclerotic effect by enhancing the biological functions of HDL without changing circulating HDL cholesterol levels. Thus, HDL-targeting therapy has significant atheroprotective potential, as it uses lipid transporter-targeting agents, and may prove to be a therapeutic tool for atherosclerotic cardiovascular diseases. PMID:25349649

Uehara, Yoshinari; Saku, Keijiro



Native and oxidized low density lipoproteins modulate mesangial cell apoptosis.  


Hyperlipidemia has been demonstrated to contribute to hypercellularity of the mesangium in experimental animal models of glomerulosclerosis. We studied whether it also has the potential to convert a hypercellular mesangium into a hypocellular one by inducing mesangial cell (MC) apoptosis. Low density lipoprotein (LDL) enhanced (P < 0.001) mouse mesangial cell (MMC) proliferation at lower concentrations (control, 10.3 +/- 0.3 vs. LDL 100 micrograms/ml, 24.2 +/- 0.3 x 10(4) cells/ml) but augmented (P < 0.001) apoptosis at higher concentrations (control, 5.6 +/- 0.5% vs. LDL, 500 micrograms/ml 26.2 +/- 3.4% apoptotic cells/field). Oxidized (OX) LDL enhanced MMC apoptosis in concentrations of 50 to 200 micrograms/dl. There was a direct relationship between MMC apoptosis and oxidation of LDL as judged by measuring thiobarbituric acid reactive species (TBARS). Since superoxide dismutase (SOD) attenuated (P < 0.001) LDL-induced MMC apoptosis, it seems to be mediated through the generation of free radicals by mesangial cells (control, 4.3 +/- 1.5%; LDL, 200 micrograms/ml, 19.4 +/- 0.5%; LDL + SOD, 8.1 +/- 1.3% apoptotic cells/field). LDL also induced a similar effect on human mesangial cells. These studies were further confirmed by DNA fragment assays and ELISA for programmed cell death. LDL treated cells also showed enhanced mRNA expression for RSG-2, a marker for active cell death. These in vitro results provide a basis for the speculation that LDL has the potential to cause an initial hypercellular and subsequent hypocellular mesangium in the course of the development of glomerulosclerosis. PMID:8914027

Sharma, P; Reddy, K; Franki, N; Sanwal, V; Sankaran, R; Ahuja, T S; Gibbons, N; Mattana, J; Singhal, P C



Biodegradable synthetic high-density lipoprotein nanoparticles for atherosclerosis  

PubMed Central

Atherosclerosis remains one of the most common causes of death in the United States and throughout the world because of the lack of early detection. Macrophage apoptosis is a major contributor to the instability of atherosclerotic lesions. Development of an apoptosis targeted high-density lipoprotein (HDL)-mimicking nanoparticle (NP) to carry contrast agents for early detection of vulnerable plaques and the initiation of preventative therapies that exploit the vascular protective effects of HDL can be attractive for atherosclerosis. Here, we report the construction of a synthetic, biodegradable HDL-NP platform for detection of vulnerable plaques by targeting the collapse of mitochondrial membrane potential that occurs during apoptosis. This HDL mimic contains a core of biodegradable poly(lactic-co-glycolic acid), cholesteryl oleate, and a phospholipid bilayer coat that is decorated with triphenylphosphonium (TPP) cations for detection of mitochondrial membrane potential collapse. The lipid layer provides the surface for adsorption of apolipoprotein (apo) A-I mimetic 4F peptide, and the core contains diagnostically active quantum dots (QDs) for optical imaging. In vitro uptake, detection of apoptosis, and cholesterol binding studies indicated promising detection ability and therapeutic potential of TPP-HDL-apoA-I-QD NPs. In vitro studies indicated the potential of these NPs in reverse cholesterol transport. In vivo biodistribution and pharmacokinetics indicated favorable tissue distribution, controlled pharmacokinetic parameters, and significant triglyceride reduction for i.v.-injected TPP-HDL-apoA-I-QD NPs in rats. These HDL NPs demonstrate excellent biocompatibility, stability, nontoxic, and nonimmunogenic properties, which prove to be promising for future translation in early plaque diagnosis and might find applications to prevent vulnerable plaque progression. PMID:23671083

Marrache, Sean; Dhar, Shanta



High-density lipoprotein and atherosclerosis: Roles of lipid transporters  

PubMed Central

Various previous studies have found a negative correlation between the risk of cardiovascular events and serum high-density lipoprotein (HDL) cholesterol levels. The reverse cholesterol transport, a pathway of cholesterol from peripheral tissue to liver which has several potent antiatherogenic properties. For instance, the particles of HDL mediate to transport cholesterol from cells in arterial tissues, particularly from atherosclerotic plaques, to the liver. Both ATP-binding cassette transporters (ABC) A1 and ABCG1 are membrane cholesterol transporters and have been implicated in mediating cholesterol effluxes from cells in the presence of HDL and apolipoprotein A-I, a major protein constituent of HDL. Previous studies demonstrated that ABCA1 and ABCG1 or the interaction between ABCA1 and ABCG1 exerted antiatherosclerotic effects. As a therapeutic approach for increasing HDL cholesterol levels, much focus has been placed on increasing HDL cholesterol levels as well as enhancing HDL biochemical functions. HDL therapies that use injections of reconstituted HDL, apoA-I mimetics, or full-length apoA-I have shown dramatic effectiveness. In particular, a novel apoA-I mimetic peptide, Fukuoka University ApoA-I Mimetic Peptide, effectively removes cholesterol via specific ABCA1 and other transporters, such as ABCG1, and has an antiatherosclerotic effect by enhancing the biological functions of HDL without changing circulating HDL cholesterol levels. Thus, HDL-targeting therapy has significant atheroprotective potential, as it uses lipid transporter-targeting agents, and may prove to be a therapeutic tool for atherosclerotic cardiovascular diseases. PMID:25349649

Uehara, Yoshinari; Saku, Keijiro



Interaction of very-low-density, intermediate-density, and low-density lipoproteins with human arterial wall proteoglycans.  


The specific interaction of lipoproteins with arterial wall constituents, particularly proteoglycans (APG), is believed to play an important role in the development of atherosclerosis. The objective of this study was to examine the interaction of apolipoprotein B (apoB) containing lipoprotein subfractions (VLDL1, Sf 60 to 400; VLDL2, Sf 20 to 60; IDL1, Sf 16 to 20; IDL2, Sf 12 to 16; LDLA, Sf 8 to 12; and LDLB, Sf 0 to 8) prepared by cumulative density gradient centrifugation with chondroitin sulfate-rich APG. Eighteen subjects were studied, and a similar pattern of interaction between the lipoprotein species and APG was found in all. The order of reactivity (as measured by increased turbidity due to insoluble complex formation) was IDL Sf 12 to 16 > or = LDL Sf 8 to 12 > LDL Sf 0 to 8 > IDL Sf 16 to 20 > VLDL Sf 20 to 60 > VLDL Sf 60 to 400. When the subjects were divided on the basis of their LDL subfraction profile, the extent of insoluble complex formation was highest in the group in which small, dense LDLIII was predominant; intermediate in the group whose LDL was mainly LDLII; and lowest in the group with a high proportion of LDLI (the mean reactivity, AU at 600 nm. of APG with IDL Sf 12 to 16 and LDL Sf 8 to 12 was 0.66; 0.62 and 0.46, 0.43 and 0.20, and 0.21 for the three groups, respectively). Fibrate lipid-lowering treatment decreased the percentage of LDLIII and increased the percentage of LDLI within total LDL and reduced the reactivity of all apoB-containing lipoprotein fractions toward APG. Sialic acid content varied in different lipoprotein subfractions, being the highest in VLDL and lowest in LDL. However, across lipoprotein species, it did not significantly correlate with APG-binding reactivity, suggesting that other factors are important in determining the interaction of lipoproteins with APG. Modification of LDL arginine and lysine residues abolished the ability of the lipoprotein to interact with APG, a finding that supports the hypothesis that the interaction is dependent on key positively charged amino acids on apoB. These findings demonstrate that (1) the overall reactivity of apoB-containing lipoproteins is greatest in individuals with small, dense LDL and (2) within an individual, IDL of Sf 12 to 16 is the most reactive species, and this may in part explain the positive correlation between IDL and risk of coronary heart disease. PMID:9409221

Anber, V; Millar, J S; McConnell, M; Shepherd, J; Packard, C J



Increased Very Low Density Lipoprotein Secretion, Hepatic Steatosis, and Insulin Resistance  

PubMed Central

Insulin resistance (IR) not only affects regulation of carbohydrate metabolism, but all aspects of lipid and lipoprotein metabolism. IR is associated with increased secretion of very low density lipoproteins (VLDL) and increased plasma triglycerides, as well as hepatic steatosis, despite the increased VLDL secretion. Here, we link IR with increased VLDL secretion and hepatic steatosis at both the physiologic and molecular levels. Increased VLDL secretion, together with the downstream effects on high density lipoprotein cholesterol and low density lipoprotein size is pro-atherogenic. Hepatic steatosis is a risk for steatohepatitis and cirrhosis. Understanding the complex inter-relationship between IR and these abnormalities of liver lipid homeostasis may provide insights relevant to new therapies for these increasing clinical problems. PMID:21616678

Choi, Sung Hee; Ginsberg, Henry N



Dietary ?-cyclodextrin lowers low-density lipoprotein cholesterol and alters plasma fatty acid profile in low-density lipoprotein receptor knockout mice on a high-fat diet  

Microsoft Academic Search

High dietary intake of saturated fat and cholesterol, and elevated low-density lipoprotein cholesterol levels are some of the modifiable risk factors for cardiovascular disease. ?-Cyclodextrin (a-CD) when given orally has been shown in rats to increase fecal saturated fat excretion and to reduce blood total cholesterol levels in obese hypertriglyceridemic subjects with type 2 diabetes mellitus. In this study, the

Elke Maria Wagner; Kai-Lin Catherine Jen; Joseph Donald Artiss; Alan Thomas Remaley



Initial low-density lipoprotein response to statin therapy predicts subsequent low-density lipoprotein response to the addition of ezetimibe  

Microsoft Academic Search

This small retrospective study confirms the hypothesis that patients who are hyporesponders to statin therapy are hyper-responders to ezetimibe therapy and may help identify a patient population in whom ezetimibe would be particularly effective in lowering low-density lipoprotein cholesterol.

Paul E. Ziajka; Mary Reis; Sandra Kreul; Helen King



High-density lipoprotein and transport of cholesterol and triglyceride in blood.  


High-density lipoproteins (HDL) contain approximately 25% of the cholesterol and <5% of the triglyceride in the plasma of human blood. However, the dynamic exchange of lipids and lipid-binding proteins is not revealed by simply considering the mass of material at any point in time. HDL are the most complex of lipoprotein species with multiple protein constituents, which facilitate cholesterol secretion from cells, cholesterol esterification in plasma, and transfer of cholesterol to other lipoproteins and to the liver for excretion. They also play a major role in triglyceride transport by providing for activation of lipoprotein lipase, exchange of triglyceride among the lipoproteins, and removal of triglyceride rich remnants of chylomicrons and very-low-density lipoproteins after lipase action. In addition, antioxidative enzymes and phospholipid transfer proteins are important components of HDL. Many of the proteins of HDL are exchangeable with other lipoproteins, including chylomicrons and very-low-density lipoproteins. The constantly changing content of lipids and apolipoproteins in HDL particles generate a series of structures that can be analyzed by using separation techniques that depend on size or charge of the particles. Interaction of these various structures can be very different with cell surfaces depending on the size or apolipoprotein content. A series of different transport proteins preferentially exchange lipids with specific structures among the HDL but interact poorly or not at all with others. The role of these differing forms of HDL and their interactions with cells and other lipoprotein species in plasma is the subject of intense study stimulated by the potential for reducing atherogenesis. The strength of this is only partially indicated by the correlation of higher total levels of the HDL particles with reduced incidence of vascular disease in various clinical trials and epidemiological studies. PMID:21291664

Brown, William Virgil



PPAR? is a very low-density lipoprotein sensor in macrophages  

PubMed Central

Although triglyceride-rich particles, such as very low-density lipoprotein (VLDL), contribute significantly to human atherogenesis, the molecular basis for lipoprotein-driven pathogenicity is poorly understood. We demonstrate that in macrophages, VLDL functions as a transcriptional regulator via the activation of the nuclear receptor peroxisome proliferator-activated receptor ?. The signaling components of native VLDL are its triglycerides, whose activity is enhanced by lipoprotein lipase. Generation of peroxisome proliferator-activated receptor ? null macrophages verifies the absolute requirement of this transcription factor in mediating the VLDL response. Thus, our data reveal a pathway through which dietary triglycerides and VLDL can directly regulate gene expression in atherosclerotic lesions. PMID:12540828

Chawla, Ajay; Lee, Chih-Hao; Barak, Yaacov; He, Weimin; Rosenfeld, John; Liao, Debbie; Han, Jungyeob; Kang, Heonjoong; Evans, Ronald M.



Degradation of Cationized Low Density Lipoprotein and Regulation of Cholesterol Metabolism in Homozygous Familial Hypercholesterolemia Fibroblasts  

Microsoft Academic Search

Cultured fibroblasts derived from patients with homozygous familial hypercholesterolemia, which lack functional low density lipoprotein (LDL) receptors, fail to bind, take up, or degrade the lipoprotein with high affinity; therefore LDL-cholesterol is not made available for suppression of cholesterol synthesis or activation of cholesteryl ester formation. When LDL was given a positive charge by reaction with N,N-dimethyl-1,3-propanediamine (cationized LDL), the

Sandip K. Basu; Joseph L. Goldstein; Richard G. W. Anderson; Michael S. Brown



Increased Low-Density Lipoprotein S-Homocysteinylation in Chronic Kidney Disease  

Microsoft Academic Search

Background: Since low-density lipoprotein (LDL) S-homocysteinylation has been recently reported to enhance atherogenicity of lipoprotein, we have investigated the levels of homocysteine (Hcy) linked to LDL in chronic proteinuric patients in which lipid abnormalities highly contribute to the excess of morbidity and mortality. Methods: We used capillary electrophoresis to measure LDL-bound thiol Hcy, cysteine (Cys), cysteinylglycine (Cys-Gly), glutathione (GSH), and

Angelo Zinellu; Giacomina Loriga; Bastianina Scanu; Elisabetta Pisanu; Manuela Sanna; Luca Deiana; Andrea Ercole Satta; Ciriaco Carru



Ath1, a Gene Determining Atherosclerosis Susceptibility and High Density Lipoprotein Levels in Mice  

Microsoft Academic Search

High density lipoprotein (HDL) is the major plasma lipoprotein found in mice fed normal laboratory chow containing 4% fat. When female mice from some inbred strains, such as C57BL\\/6, are fed a high fat diet (1.25% cholesterol, 15% fat, and 0.5% cholic acid), the levels of HDL-cholesterol decrease by about 50%, and lipid staining lesions form in the aorta within

Beverly Paigen; Diane Mitchell; Karen Reue; Arlene Morrow; Aldons J. Lusis; Renee C. Leboeuf



Lipoprotein binding and endosomal itinerary of the low density lipoprotein receptor-related protein in rat liver  

SciTech Connect

The high affinity of {sup 45}Ca binding to the low density lipoprotein receptor (LDL-R) and the LDL-R-related protein (LRP) was utilized to study the subcellar distribution of these two proteins in rat liver. Like the LDL-R, LRP was manyfold enriched in rat liver endosomal membranes with a relative distribution in early and late endosomal compartments consistent with recycling between endosomes and the cell surface. The high concentration of LRP in hepatic endosomal membranes greatly facilitated demonstration of Ca-dependent binding of apolipoprotein E- and B-containing lipoproteins in ligand blots. LRP was severalfold more abundant than the LDL-R in hepatic parenchymal cells, showed extensive degradation in hepatic endosomes, and was found in high concentrations in the Golgi apparatus and endoplasmic reticulum. These data suggest a high a rate of synthesis of LRP that appeared to be unaffected by treatment of rats with estradiol. The repeating cysteine-rich A-motif found in the ligand-binding domain of LRP appeared to be responsible for Ca binding by LRP, LDL-R, and complement factor C9 and accounted for immunological cross-reactivity among these proteins. The data suggest an extensive proteolytic processing of this protein and are consistent with a functional role of LRP in lipoprotein metabolism.

Lund, H.; Takahashi, K.; Hamilton, R.L.; Havel, R.J. (Univ. of California, San Francisco (USA))



Catalytically inactive lipoprotein lipase expression in muscle of transgenic mice increases very low density lipoprotein uptake: direct evidence that lipoprotein lipase bridging occurs in vivo.  


Lipoprotein lipase (LPL) is the central enzyme in plasma triglyceride hydrolysis. In vitro studies have shown that LPL also can enhance lipoprotein uptake into cells via pathways that are independent of catalytic activity but require LPL as a molecular bridge between lipoproteins and proteoglycans or receptors. To investigate whether this bridging function occurs in vivo, two transgenic mouse lines were established expressing a muscle creatine kinase promoter-driven human LPL (hLPL) minigene mutated in the catalytic triad (Asp156 to Asn). Mutated hLPL was expressed only in muscle and led to 3,100 and 3,500 ng/ml homodimeric hLPL protein in post-heparin plasma but no hLPL catalytic activity. Less than 5 ng/ml hLPL was found in preheparin plasma, indicating that proteoglycan binding of mutated LPL was not impaired. Expression of inactive LPL did not rescue LPL knock-out mice from neonatal death. On the wild-type (LPL2) background, inactive LPL decreased very low density lipoprotein (VLDL)-triglycerides. On the heterozygote LPL knock-out background (LPL1) background, plasma triglyceride levels were lowered 22 and 33% in the two transgenic lines. After injection of radiolabeled VLDL, increased muscle uptake was observed for triglyceride-derived fatty acids (LPL2, 1.7x; LPL1, 1.8x), core cholesteryl ether (LPL2, 2.3x; LPL1, 2.7x), and apolipoprotein (LPL1, 1.8x; significantly less than cholesteryl ether). Skeletal muscle from transgenic lines had a mitochondriopathy with glycogen accumulation similar to mice expressing active hLPL in muscle. In conclusion, it appears that inactive LPL can act in vivo to mediate VLDL removal from plasma and uptake into tissues in which it is expressed. PMID:9811888

Merkel, M; Kako, Y; Radner, H; Cho, I S; Ramasamy, R; Brunzell, J D; Goldberg, I J; Breslow, J L



Plasma lipoproteins in familial lecithin: cholesterol acyltransferase deficiency: physical and chemical studies of low and high density lipoproteins  

PubMed Central

Low density lipoproteins (LDL) and high density lipoproteins (HDL) from the plasma of patients with familial lecithin: cholesterol acyltransferase (LCAT) deficiency have been characterized by gel filtration, analytical ultracentrifugation, and gel electrophoresis, and their relative content of lipid and protein has been determined. The LDL of d 1.019-1.063 g/ml show marked heterogeneity. A subfraction of the LDL emerges from columns of 2% agarose gel with the void volume, has corrected flotation rates (Sf°) in the range of 20-400, and contains 4-10 times as much unesterified cholesterol, phosphatidylcholine, and triglyceride per mg protein as normal LDL. A major subfraction of the LDL emerges from the gel in the same general position as normal LDL, but exhibits somewhat higher flotation rates and contains 1.5-3 times as much unesterified cholesterol and phosphatidylcholine and 13 times as much triglyceride per mg protein. The HDL, shown to be heterogeneous in earlier studies, are mainly comprised of molecules which have flotation rates of F1.20 3-20, migrate in the ?1-?2 region on electrophoresis, and contain about 12 times as much unesterified cholesterol and 5 times as much phosphatidylcholine per mg protein as normal HDL. Smaller molecules are also detected, which have flotation rates of F1.20 0-3, migrate in the prealbumin region on electrophoresis, and contain only slightly more unesterified cholesterol and phosphatidylcholine per mg protein than normal HDL. Images PMID:5552410

Norum, Kaare R.; Glomset, John A.; Nichols, Alex V.; Forte, Trudy



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

PubMed Central

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

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



Cholesterol transfer from low density lipoproteins to reconstituted high density lipoproteins is determined by the properties and concentrations of both particles.  


Cholesterol spontaneously transfers from low density lipoproteins (LDL) to high density lipoproteins (HDL). This transfer is important physiologically as it supplies the major portion of cholesterol for the lecithin:cholesterol acyltransferase reaction and is one mechanism for the reduction of atherogenic LDL cholesterol. The objective of this work was to examine the properties of both HDL and LDL which modulate cholesterol transfer, as well as to obtain the relevant kinetic constants for the transfer at concentrations of lipoproteins approaching those existing in vivo. To examine the effects of HDL structural parameters on cholesterol transfer, we prepared reconstituted HDL particles with saturated or unsaturated phospholipid, with apolipoprotein AI or apolipoprotein AII, with increasing size and phospholipid content, and with increasing initial contents of cholesterol. We also prepared five LDL subfractions of variable density and size. The kinetics of cholesterol mass transfer were measured by incubating LDL with rHDL at 37 degrees C, separating the lipoproteins by dextran sulfate/Mg2+ precipitation of LDL at timed intervals, and analyzing rHDL cholesterol content. The cholesterol content of rHDL at equilibrium, Ceq, and the half-time for transfer, t1/2, as well as the ratio of the lipid surface areas of LDL to rHDL were used in the analysis of the kinetic data by the aqueous diffusion model for lipid transfer developed by Nichols and Pagano [(1982) Biochemistry 21, 1720-1726]. The only variables that significantly affect the C(eq) and/or t1/2 are the phospholipid content and composition of the rHDL and the size or density of the LDL particles.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7766638

Bottum, K; Jonas, A



Oxidized Low-Density Lipoproteins, Autoantibodies against Oxidized Low-Density Lipoproteins and Carotid Intima Media Thickness in a Clinically Healthy Population  

Microsoft Academic Search

Background: Oxidized low-density lipoproteins (oxLDLs) play an important role in the progress of atherosclerosis. Autoantibodies (oxLDL Ab) against oxLDLs may reflect the extent of LDL oxidation in vivo. Our aim was to investigate the correlation between oxLDLs, oxLDL Ab and intima media thickness of the common carotid arteries (CCA-IMT) in a clinically healthy population. Methods: Two hundred subjects were recruited,

Haw-Wen Chen; Ching-Ling Kuo; Ching-Shan Huang; Shou-Jen Kuo; Chin-San Liu



High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from framingham to the veterans affairs high-density lipoprotein intervention trial  

Microsoft Academic Search

The Framingham Heart Study found that high-density lipoprotein cholesterol (HDL-C) was the most potent lipid predictor of coronary artery disease risk in men and women >49 years of age. The Air Force\\/Texas Coronary Atherosclerosis Prevention Study (AFCAPS\\/TexCAPS), in which subjects were randomized to treatment with lovastatin or placebo, also reported a striking benefit of treatment, particularly in patients with HDL-C

William E Boden



Overproduced interleukin 6 decreases blood lipid levels via upregulation of very-low-density lipoprotein receptor  

Microsoft Academic Search

BackgroundInterleukin 6 (IL6) blockade raises blood lipid levels in patients with rheumatoid arthritis.ObjectiveTo examine the influence of IL6 on lipid metabolism.MethodsVascular smooth muscle cells (VSMC) were cultured in the presence of IL6, soluble IL6 receptor (sIL6R), IL6+sIL6R or tumour necrosis factor ? (TNF?) for 24 h. After culture, the expression of very-low-density lipoprotein receptor (VLDLR), low-density lipoprotein receptor (LDLR) and

Misato Hashizume; Hiroto Yoshida; Nobuo Koike; Miho Suzuki; Masahiko Mihara



Impaired trafficking of the very low density lipoprotein receptor caused by missense mutations associated with dysequilibrium syndrome.  


Dysequilibrium syndrome (DES, OMIM 224050) is a genetically heterogeneous condition that combines autosomal recessive non-progressive cerebellar ataxia with mental retardation. The subclass dysequilibrium syndrome type 1 (CAMRQ1) has been attributed to mutations in the VLDLR gene encoding the very low density lipoprotein receptor (VLDLR). This receptor is involved in the Reelin signaling pathway that guides neuronal migration in the cerebral cortex and cerebellum. Three missense mutations (c.1459G>T; p.D487Y, c.1561G>C; p.D521H and c.2117G>T; p.C706F) have been previously identified in VLDLR gene in patients with DES. However, the functional implications of those mutations are not known and therefore we undertook detailed functional analysis to elucidate the cellular mechanisms underlying their pathogenicity. The mutations have been generated by site-directed mutagenesis and then expressed in cultured cell lines. Confocal microscopy and biochemical analysis have been employed to examine the subcellular localization and functional activities of the mutated proteins relative to wild type. Our results indicate that the three missense mutations lead to defective intracellular trafficking and ER retention of the mutant VLDLR protein. This trafficking impairment prevents the mutants from reaching the plasma membrane and binding exogenous Reelin, the initiating event in Reelin signaling. Collectively, our results provide evidence that ER quality control is involved in the functional inactivation and underlying pathogenicity of these DES-associated mutations in the VLDLR. PMID:25173816

Kizhakkedath, Praseetha; Loregger, Anke; John, Anne; Bleijlevens, Boris; Al-Blooshi, Ali S; Al-Hosani, Ahmed H; Al-Nuaimi, Ahmed M; Al-Gazali, Lihadh; Zelcer, Noam; Ali, Bassam R



Catalytically Inactive Lipoprotein Lipase Expression in Muscle of Transgenic Mice Increases Very Low Density Lipoprotein Uptake: Direct Evidence that Lipoprotein Lipase Bridging Occurs in vivo  

Microsoft Academic Search

Lipoprotein lipase (LPL) is the central enzyme in plasma triglyceride hydrolysis. In vitro studies have shown that LPL also can enhance lipoprotein uptake into cells via pathways that are independent of catalytic activity but require LPL as a molecular bridge between lipoproteins and proteoglycans or receptors. To investigate whether this bridging function occurs in vivo, two transgenic mouse lines were

Martin Merkel; Yuko Kako; Herbert Radner; Irene S. Cho; Ravi Ramasamy; John D. Brunzell; Ira J. Goldberg; Jan L. Breslow



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

SciTech Connect

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

Sorci-Thomas, M.G.



Lipoprotein lipase mediates an increase in the selective uptake of high density lipoprotein-associated cholesteryl esters by hepatic cells in culture  

Microsoft Academic Search

In this study the effect of lipoprotein lipase (LPL) on the selective uptake of high density lipoprotein (HDL) cholesteryl esters (CE) by hepatic cells was investi- gated. Human HDL 3 (d 1.125-1.21 g\\/ml) was radiolabeled with 125 I in the protein moiety and with 3 H in the CE moiety. LPL was prepared from bovine milk. Human hepatocytes in primary

Franz Rinninger; Tatjana Kaiser; W. Alexander Mann; Nicolette Meyer; Heiner Greten; Ulrike Beisiegel


High Density Lipoprotein-mediated Cholesterol Uptake and Targeting to Lipid Droplets in Intact L-cell Fibroblasts  

E-print Network

High Density Lipoprotein-mediated Cholesterol Uptake and Targeting to Lipid Droplets in Intact L, dehydroergosterol and NBD-cho- lesterol, were used to examine high density lipoprotein- mediated cholesterol uptake, of these sterols differed >100-fold, suggesting significant differences in uptake pathways. NBD-cholesterol uptake

So, Peter


Influence of Honey on the Suppression of Human Low Density Lipoprotein (LDL) Peroxidation (In Vitro)  

Microsoft Academic Search

The antioxidant activity of four honey samples from different floral sources (Acacia, Coriander, Sider and Palm) were evaluated with three different assays; DPPH free radical scavenging assay, superoxide anion generated in xanthine-xanthine oxidase (XOD) system and low density lipoprotein (LDL) peroxidation assay. The dark Palm and Sider honeys had the highest antioxidant activity in the DPPH assay. But all the

Ahmed G. Hegazi; Faten K. Abd El-Hady



Low density lipoprotein particle size and risk factors of insulin resistance syndrome  

Microsoft Academic Search

The present study aimed to examine the association between low density lipoprotein (LDL) particle size and glucose and insulin variables and with other risk factors that have been related to insulin resistance syndrome. LDL particle size was determined in two groups of subjects who participated in the first examination of the Jerusalem Diabetes Study and who were invited to be

Yechiel Friedlander; Miriam Kidron; Muriel Caslake; Tracey Lamb; Michael McConnell; Hanoch Bar-On



Hemoglobin Induced Apolipoprotein B Crosslinking in Low-Density Lipoprotein Peroxidation  

Microsoft Academic Search

Oxidative modification of human low-density lipoprotein (LDL) is thought to play a major role in the development of atherosclerosis. Free hemin, hemoglobin, myoglobin, and horseradish peroxidase (HRP) were reported in different studies as promoters of LDL lipid oxidation. Based on our previous finding that hemin induced oxidative crosslinking of the LDL protein, apolipoprotein B (apo B) (Y. I. Miller and

Yury I. Miller; Yana Felikman; Nurith Shaklai



Total and High-Density Lipoprotein Cholesterol in Adults with Mental Retardation.  

ERIC Educational Resources Information Center

The study evaluated the total cholesterol and high density lipoprotein cholesterol of 40 adults (mean age 37.5 years) with mental retardation residing at an intermediate care facility. Results indicated that 59 percent of the males and 68 percent of the females were at moderate to high risk for coronary heart disease. (DB)

Rimmer, James H.; Kelly, Luke E.



Glycemic Index and Serum High-Density Lipoprotein Cholesterol Concentration Among US Adults  

Microsoft Academic Search

Background: Dietary glycemic index, an indicator of the ability of the carbohydrate to raise blood glucose lev- els, and glycemic load, the product of glycemic index and carbohydrate intake, have been positively related to risk of coronary heart disease. However, the relationships be- tween glycemic index and glycemic load and high- density lipoprotein cholesterol (HDL-C) concentration in the US population

Earl S. Ford; Simin Liu



In vitro incorporation of radiolabeled cholesteryl esters into high and low density lipoproteins  

SciTech Connect

We have developed and validated a method for in vitro incorporation of radiolabeled cholesteryl esters into low density (LDL) and high density lipoproteins (HDL). Radiolabeled cholesteryl esters dissolved in absolute ethanol were mixed with LDL or HDL in the presence of lipoprotein-deficient serum (LPDS) as a source of core lipid transfer activity. The efficiency of incorporation was dependent on: (a) the core lipid transfer activity and quantity of LPDS, (b) the mass of added radiolabeled cholesteryl esters, (c) the length of incubation, and (d) the amount of acceptor lipoprotein cholesterol. The tracer incorporation was documented by repeat density gradient ultracentrifugation, agarose gel electrophoresis, and precipitation with heparin-MnCl2. The radiolabeling conditions did not affect the following properties of the lipoproteins: (1) chemical composition, (2) electrophoretic mobility on agarose gels, (3) hydrated density, (4) distribution of apoproteins on SDS gels, (5) plasma clearance rates, and (6) immunoprecipitability of HDL apoproteins A-I and A-II. Rat HDL containing radiolabeled cholesteryl esters incorporated in vitro had plasma disappearance rates identical to HDL radiolabeled in vivo.

Terpstra, A.H.; Nicolosi, R.J.; Herbert, P.N. (Brown Univ. Program in Medicine, Providence, RI (USA))



Autoantibodies Against Oxidized Low Density Lipoprotein in Patients With Angiographically Verified Coronary Artery Disease  

Microsoft Academic Search

Oxidation of low density lipoproteins (LDL) obviously plays an important role in the pathogenesis of atherosclerosis. The purpose of the study was to determine whether antibodies against oxidized LDL are associated with coronary artery disease (CAD). We determined the serum levels of antibodies against copper-oxidized LDL by enzyme-linked immunosorbent assay in 58 patients with angiographically verified CAD and 34 controls

Terho Lehtimaki; Saara Lehtinen; Tiina Solakivi; Matti Nikkila; Olli Jaakkola; Hannu Jokela; Seppo Yla; Jukka S. Luoma; Timo Koivula; Tapio Nikkari


The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?  

Microsoft Academic Search

There is unequivocal evidence of an inverse association between plasma high-density lipoprotein (HDL) cholesterol concentrations and the risk of cardiovascular disease, a finding that has led to the hypothesis that HDL protects from atherosclerosis. This review details the experimental evidence for this \\

M. Vergeer; A. G. Holleboom; J. J. P. Kastelein; J. A. Kuivenhoven



Boca-dependent maturation of b-propeller/EGF modules in low-density lipoprotein receptor  

E-print Network

Boca-dependent maturation of b-propeller/EGF modules in low-density lipoprotein receptor proteins ortholog, Mesoderm development, in the mouse. All LDLRs have at least one six-bladed b-propeller domain is specifically required for the maturation of these b-propeller/EGF modules through the secretory pathway

Springer, Timothy A.


Differential density lipoprotein profiling for the characterization of Lipoprotein(a)  

E-print Network

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 22 Third component influence in density gradient formation. Na- BiEDTA density gradient formed with serum sample diluted in: A)water; B)PBS-p; C)PBS-g . . . . . . . . . . . . . . . . . . . . . . 69 xiii FIGURE Page 23 Coomasie Blue-stained SDS... electrolyte consisted of 13 mM sodium borate, 3.5 mM SDS , and 20% (v/v) acetonitrile, pH 9.25. Under these conditions this Lp(a) sample has an effective mobility of -17x10-5 cm2/Vs . . . . . . . . . . . . . . . . . . . . . . 88 34 Electropherogram of apo...

Espinosa Garcia, Irma Leticia



Cholesteryl ester transfer activity in plasma measured by using solid-phase-bound high-density lipoprotein  

SciTech Connect

We studied the ability of lipid-transfer factors in plasma to promote transfer, to endogenous lipoproteins, of (/sup 3/H)cholesteryl ester from high-density lipoprotein (HDL) covalently bound to Sepharose 4B beads. After incubation for 2 h at 37 degrees C, 12 to 14% of the (/sup 3/H)cholesteryl ester had been transferred to the lipoproteins of the plasma, in the proportions 57% to HDL and 43% to low- and very-low-density lipoproteins. This process was a function of the amount of plasma present and was stimulated by addition of partly purified lipid-transfer protein. Transfer also depended on the concentration of donor HDL but was independent of the amount of acceptor lipoprotein. This simple evaluation of cholesteryl ester transfer does not require removal of lipoproteins from the plasma before incubation.

Sparks, D.L.; Frohlich, J.; Cullis, P.; Pritchard, P.H.



Association between Hepatitis C Virus and Very-Low-Density Lipoprotein (VLDL)\\/LDL Analyzed in Iodixanol Density Gradients  

Microsoft Academic Search

Hepatitis C virus (HCV) RNA circulates in the blood of persistently infected patients in lipoviroparticles (LVPs), which are heterogeneous in density and associated with host lipoproteins and antibodies. The vari- ability and lability of these virus-host complexes on fractionation has hindered our understanding of the structure of LVP and determination of the physicochemical properties of the HCV virion. In this

Søren U. Nielsen; Margaret F. Bassendine; Alastair D. Burt; Caroline Martin; Wanna Pumeechockchai; Geoffrey L. Toms



Negatively cooperative binding of high-density lipoprotein to the HDL receptor SR-BI.  


Scavenger receptor class B, type I (SR-BI), is a high-density lipoprotein (HDL) receptor, which also binds low-density lipoprotein (LDL), and mediates the cellular selective uptake of cholesteryl esters from lipoproteins. SR-BI also is a coreceptor for hepatitis C virus and a signaling receptor that regulates cell metabolism. Many investigators have reported that lipoproteins bind to SR-BI via a single class of independent (not interacting), high-affinity binding sites (one site model). We have reinvestigated the ligand concentration dependence of (125)I-HDL binding to SR-BI and SR-BI-mediated specific uptake of [(3)H]CE from [(3)H]CE-HDL using an expanded range of ligand concentrations (<1 ?g of protein/mL, lower than previously reported). Scatchard and nonlinear least-squares model fitting analyses of the binding and uptake data were both inconsistent with a single class of independent binding sites binding univalent lipoprotein ligands. The data are best fit by models in which SR-BI has either two independent classes of binding sites or one class of sites exhibiting negative cooperativity due to either classic allostery or ensemble effects ("lattice model"). Similar results were observed for LDL. Application of the "infinite dilution" dissociation rate method established that the binding of (125)I-HDL to SR-BI at 4 °C exhibits negative cooperativity. The unexpected complexity of the interactions of lipoproteins with SR-BI should be taken into account when interpreting the results of experiments that explore the mechanism(s) by which SR-BI mediates ligand binding, lipid transport, and cell signaling. PMID:21254782

Nieland, Thomas J F; Xu, Shangzhe; Penman, Marsha; Krieger, Monty



Regulation of low density lipoprotein receptor activity in freshly isolated human lymphocytes.  

PubMed Central

Circulating human lymphocytes freshly isolated from venous blood of 15 normal subjects exhibited a low capacity to bind, take up, and degrade 125I-labeled low density lipoprotein (LDL). However, when these cells were incubated for 72 h in the absence of lipoproteins, they gradually acquired in increased number of high affinity cell surface receptors for LDL. The increase in the number of LDL receptors was associated with a 16-fold increase in the rate at which the cells were able to take up and degrade the lipoprotein. The LDL binding and degradation processes that developed in normal lymphocytes exhibited the following characteristics; (a) high affinity (saturation was achieved at LDL concentrations below 50 mug protein/ml); (b) specificity (unlabeled LDL was much more effective than human high density lipoprotein or other plasma proteins in competing with 125I-LDL for binding to the LDL receptor); and(c) feedback regulation (the increase in the number of LDL receptors that appeared after incubation of freshly isolated lymphocytes in lipoprotein-deficient medium was prevented by exposure of the cells to either LDL or a mixture of 25-hydroxycholesterol plus cholesterol but not to HDL). Freshly isolated lymphocytes obtaine from three subjects with the homozygous form of familial hypercholesterolemia failed to develop normal amounts of LDL receptor activity when incubated in medium devoid of lipoproteins. The current data indicate: (a) that the LDL receptors that appear on the surface of cholesterol-deprived, normal human lymphocytes are genetically identical to the previously characterized LDL receptors of cultured human fibroblasts and long-term lymphoid cells and (b) that at least one cell type in the human body, the circulating human lymphocyte, has the capacity to produce a high affinity LDL receptor that mediates the cellular uptake and degradation of plasma LDL. PMID:186492

Ho, Y K; Brown, S; Bilheimer, D W; Goldstein, J L



The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B  

Microsoft Academic Search

To better define the role of environmental factors on LDL phenotypic expression, the authors determined LDL patterns in patients with acquired immunodeficiency syndrome (AIDS), and infection characterized by hypertriglyceridemia and weight loss. Similar to previous studies, plasma triglyceride levels were increased, whereas plasma cholesterol, LDL cholesterol, and HDL cholesterol levels were decreased in the AIDS subjects compared to those in

K. R. Feingold; R. M. Krauss; M. Pang; W. Doerrler; P. Jensen; C. Grunfeld



Modulation of low density lipoprotein subclasses by alimentary lipemia in control and normotriglyceridemic non-insulin-dependent diabetic subjects  

Microsoft Academic Search

Conventional factors do not fully account for the increased cardiovascular risk in NIDDM but, because of the underlying disorders in lipid metabolism, the postprandial state can be expected to induce temporary changes of a potentially atherogenic nature. The response to a 1000-kcal meal (70% lipid; 100 000 IU vitamin A) over 8 h was compared in 10 normoponderal, normotriglyceridemic NIDDM

Nebil Attia; Vincent Durlach; Jean-Louis Paul; Theophile Soni; Dina Betoulle; Anik Girard-Globa



Intact human ceruloplasmin oxidatively modifies low density lipoprotein.  

PubMed Central

Ceruloplasmin is a plasma protein that carries most of the copper found in the blood. Although its elevation after inflammation and trauma has led to its classification as an acute phase protein, its physiological role is uncertain. A frequently reported activity of ceruloplasmin is its ability to suppress oxidation of lipids. In light of the intense recent interest in the oxidation of plasma LDL, we investigated the effects of ceruloplasmin on the oxidation of this lipoprotein. In contrast to our expectations, highly purified, undegraded human ceruloplasmin enhanced rather than suppressed copper ion-mediated oxidation of LDL. Ceruloplasmin increased the oxidative modification of LDL as measured by thiobarbituric acid-reacting substances by at least 25-fold in 20 h, and increased electrophoretic mobility, conjugated dienes, and total lipid peroxides. In contrast, ceruloplasmin that was degraded to a complex containing 115- and 19-kD fragments inhibited cupric ion oxidation of LDL, as did commercial preparations, which were also degraded. However, the antioxidant capability of degraded ceruloplasmin in this system was similar to that of other proteins, including albumin. The copper in ceruloplasmin responsible for oxidant activity was not removed by ultrafiltration, indicating a tight association. Treatment of ceruloplasmin with Chelex-100 removed one of seven copper atoms per molecule and completely blocked oxidant activity. Restoration of the copper to ceruloplasmin also restored oxidant activity. These data indicate that ceruloplasmin, depending on the integrity of its structure and its bound copper, can exert a potent oxidant rather than antioxidant action on LDL. Our results invite speculation that ceruloplasmin may be in part responsible for oxidation of LDL in blood or in the arterial wall and may thus have a physiological role that is quite distinct from what is commonly believed. Images PMID:8163654

Ehrenwald, E; Chisolm, G M; Fox, P L



Relationship between lipoprotein lipase and high density lipoprotein cholesterol in mice: modulation by cholesteryl ester transfer protein and dietary status.  


Plasma lipoprotein lipase (LPL) activity correlates with high density lipoprotein (HDL) cholesterol levels in humans. However, in several mouse models created either through transgenesis or targeted inactivation of LPL, no significant changes in HDL cholesterol values have been evident. One possible explanation for this species difference could be the absence of plasma cholesteryl ester transfer protein (CETP) activity in mice. To explore this possibility and further investigate interactions between LPL and CETP modulating HDL cholesterol levels in vivo, we examined the relationship between LPL activity and HDL levels in mice expressing the simian CETP transgene, compared with littermates not carrying the CETP gene. On a chow diet, increasing LPL activity was associated with a trend towards increased HDL levels (51 +/- 29 vs. 31 +/- 4 mg/dL highest vs. lowest tertiles of LPL activity, P = 0.07) in mice expressing CETP, while no such effects were seen in the absence of CETP (65 +/- 12 vs. 61 +/- 15 mg/ dL). Furthermore, in the presence of CETP, a significant positive correlation between LPL activity and HDL cholesterol was evident (r = 0.15, P = 0.006), while in the absence of CETP no such correlation was detected (r = 0.15, P = 0.36), highlighting the interactions between LPL and CETP in vivo. When mice were challenged with a high fat, high carbohydrate diet, strong correlations between LPL activity and HDL cholesterol were seen in both the presence (r = 0.45, P = 0.03) and absence (r = 0.73, P < 0.001) of CETP. Therefore, under altered metabolic contexts, such as those induced by dietary challenge, the relation between LPL activity and HDL cholesterol may also become evident. Here we have shown that both genetic and environmental factors may modulate the association between LPL activity and HDL cholesterol, and provide explanations for the absence of any changes in HDL values in mice either transgenic or with targeted disruption of the LPL gene. PMID:9374130

Clee, S M; Zhang, H; Bissada, N; Miao, L; Ehrenborg, E; Benlian, P; Shen, G X; Angel, A; LeBoeuf, R C; Hayden, M R



Targeting Cardiovascular Risk Associated with Both Low Density and High Density Lipoproteins Using Statin–niacin Combination Therapy  

Microsoft Academic Search

Background Cardiovascular risk might be reduced by targeted changes in both low density and high density lipoprotein cholesterol (LDL-C and HDL-C). This dual strategy will require a well tolerated, effective regimen, as well as a better understanding of how HDL-C may be targeted.Design An open-label, uncontrolled, retrospective cohort study of combined statin–niacin therapy.Methods We reviewed all patients (n = 132)

Michael A. Blazing; Shilpa Saxena; John R. Guyton



Low density lipoprotein fraction assay for cardiac disease risk  


A variable rate density gradient electrophoric gel is described which separate LDL subfractions with the precision of ultracentrifugation techniques. Also, an innovative bottom inlet mixing chamber particularly useful for producing these gels is described.

Krauss, Ronald M. (Berkeley, CA); Blanche, Patricia J. (Berkeley, CA); Orr, Joseph (San Pablo, CA)



Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes.  


Lipoprotein lipase (LPL)-deficient mice have been created by gene targeting in embryonic stem cells. At birth, homozygous knockout pups have threefold higher triglycerides and sevenfold higher VLDL cholesterol levels than controls. When permitted to suckle, LPL-deficient mice become pale, then cyanotic, and finally die at approximately 18 h of age. Before death, triglyceride levels are severely elevated (15,087 +/- 3,805 vs 188 +/- 71 mg/dl in controls). Capillaries in tissues of homozygous knockout mice are engorged with chylomicrons. This is especially significant in the lung where marginated chylomicrons prevent red cell contact with the endothelium, a phenomenon which is presumably the cause of cyanosis and death in these mice. Homozygous knockout mice also have diminished adipose tissue stores as well as decreased intracellular fat droplets. By crossbreeding with transgenic mice expressing human LPL driven by a muscle-specific promoter, mouse lines were generated that express LPL exclusively in muscle but not in any other tissue. This tissue-specific LPL expression rescued the LPL knockout mice and normalized their lipoprotein pattern. This supports the contention that hypertriglyceridemia caused the death of these mice and that LPL expression in a single tissue was sufficient for rescue. Heterozygous LPL knockout mice survive to adulthood and have mild hypertriglyceridemia, with 1.5-2-fold elevated triglyceride levels compared with controls in both the fed and fasted states on chow, Western-type, or 10% sucrose diets. In vivo turnover studies revealed that heterozygous knockout mice had impaired VLDL clearance (fractional catabolic rate) but no increase in transport rate. In summary, total LPL deficiency in the mouse prevents triglyceride removal from plasma, causing death in the neonatal period, and expression of LPL in a single tissue alleviates this problem. Furthermore, half-normal levels of LPL cause a decrease in VLDL fractional catabolic rate and mild hypertriglyceridemia, implying that partial LPL deficiency has physiological consequences. PMID:8675619

Weinstock, P H; Bisgaier, C L; Aalto-Setälä, K; Radner, H; Ramakrishnan, R; Levak-Frank, S; Essenburg, A D; Zechner, R; Breslow, J L



Assembly and secretion of hepatic very-low-density lipoprotein.  

PubMed Central

In contrast to water-soluble fuels such as glucose or ketone bodies, the use of lipids as an energy source for tissues has required the development of complex structures for their transport through the aqueous plasma. In the case of endogenously synthesized triacylglycerol this is achieved by the assembly and secretion of hepatic VLDL which provides the necessary stability in an aqueous medium. An essential component of this assembly process is apo B. Dietary changes which require an increase in hepatic VLDL secretion appear to be accompanied by increases in the availability of functional apo B. Interesting questions relate to: (a) the intracellular site(s) of triacylglycerol association with apo B, and (b) the mechanism(s) by which the availability of functional apo B at this site responds to metabolic and hormonal signals which reflect dietary status and, thus, the need to secrete triacylglycerol. As regards the latter, although in some cases changes in apo B synthesis occur in response to VLDL secretion hepatic apo B mRNA levels appear to be quite stable in vitro. Intracellular switching of apo B between the secretory and degradative pathways may be important in controlling VLDL assembly and post-translational modifications of the apoprotein may also play a role by influencing its ability to bind to triacylglycerol. Transport is not the only problem associated with the utilization of a concentrated energy source such as triacylglycerol and the complex problems of waste product disposal and recycling have to be dealt with. In the case of triacylglycerol, potentially toxic waste products include atherogenic remnants and LDL. The overall problem, then, in the long-term, involves the development of a 'safe' means of utilizing triacylglycerol and this requirement accounts for much of the complexity of plasma lipoprotein metabolism. In this area, the rat could teach the human a few tricks. One of these appears to be the utilization of hepatic apo B48 rather than apo B100 for VLDL assembly in response to increases in the extrahepatic utilization of hepatically synthesized triacylglycerol. Under these conditions, the remnants of hepatic triacylglycerol utilization by peripheral tissues are cleared from the plasma much more readily via a process which seems to involve the cycling of more triacylglycerol back to the liver than that which occurs in humans. The means by which this is achieved, though, are obscure and may involve a chylomicron remnant receptor, the nature of which, itself, remains controversial.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2188646

Gibbons, G F



Very low density lipoprotein potentiates tumor necrosis factor-alpha expression in macrophages.  


High levels of the triacylglycerol-rich lipoproteins, very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) have been identified as independent risk factors for coronary heart disease, and inflammation is thought to contribute to atherosclerosis and its complications. To understand how dyslipidemia promotes inflammation, we have characterised the effects of VLDL treatment on production of tumor necrosis factor-alpha (TNF) by human monocyte-derived macrophages. VLDL strongly potentiated lipopolysaccharide (LPS)-induced expression of TNF mRNA and secretion of TNF protein. VLDL activated mitogen-activated protein kinase-ERK kinase 1/2 (MEK1/2), and potentiated LPS-induced MEK1/2 activation. The MEK1/2 inhibitor U0126 strongly diminished TNF expression, indicating that MEK1/2 plays a central role in the regulation of TNF expression. VLDL did not activate transcription factors NF-kappaB and PPAR-gamma, but it activated AP-1 at least as potently as LPS, and potentiated LPS-induced activation of AP-1. The inhibitor U0126 completely prevented this potentiation. Inhibition of AP-1 by decoy oligonucleotides abolished potentiation of TNF secretion by VLDL. In conclusion, VLDL treatment potentiates TNF expression in macrophages by activation of MEK1/2 and AP-1. These findings suggest that triacylglycerol-rich lipoproteins are involved in inflammatory processes associated with atherosclerosis. PMID:15777538

Stollenwerk, Maria M; Schiopu, Alexandru; Fredrikson, Gunilla Nordin; Dichtl, Wolfgang; Nilsson, Jan; Ares, Mikko P S



Sweet potato (Ipomoea batatas L.) leaves suppressed oxidation of low density lipoprotein (LDL) in vitro and in human subjects  

PubMed Central

Sweet potato (Ipomoea batatas L.) leaves are consumed as vegetables around the world, especially in Southeast Asia. The aim of this study was to investigate the inhibitory effect of sweet potato leaves on low-density lipoprotein oxidation in vitro and in human subjects. We compared the antioxidant activity of 8 kinds of sweet potato leaves. Every sweet potato leaf had high radical scavenging activity and prolonged a lag time for starting low-density lipoprotein oxidation in vitro. We found that sweet potato leaves contained abundant polyphenol compounds and the radical scavenging activity and prolongation rate of lag time were highly correlated with total polyphenol content. We also confirmed that thiobarbituric acid reactive substances production was increased in endothelial cell-mediated low-density lipoprotein oxidation, which was decreased by treatment with sweet potato leaves. We further measured the low-density lipoprotein oxidizability in 13 healthy volunteers after their intake of 18 g of “Suioh”, raw sweet potato leaves. “Suioh” prolonged a lag time for starting low-density lipoprotein oxidation and decreased low-density lipoprotein mobility. These results suggest that sweet potato leaves have antioxidant activity leading to the suppression of low-density lipoprotein oxidation. PMID:21562639

Nagai, Miu; Tani, Mariko; Kishimoto, Yoshimi; Iizuka, Maki; Saita, Emi; Toyozaki, Miku; Kamiya, Tomoyasu; Ikeguchi, Motoya; Kondo, Kazuo



Kinetics and mechanism of exchange of apolipoprotein C-III molecules from very low density lipoprotein particles  

Microsoft Academic Search

Transfer of apolipoprotein (apo) molecules between lipoprotein particles is an important factor in modulating the metabolism of the particles. Although the phenomenon is well established, the kinetics and molecular mechanism of passive apo exchange\\/transfer have not been defined in detail. In this study, the kinetic parameters governing the movement of radiolabeled apoC molecules from human very low density lipoprotein (VLDL)

Kathleen E Boyle; Michael C Phillips; Sissel Lund-Katz



Characterization of the low-density-lipoprotein-receptor-independent interaction of beta-very-low-density lipoprotein with rat and human parenchymal liver cells in vitro.  

PubMed Central

beta-Migrating very-low-density lipoprotein (beta-VLDL) is a cholesteryl-ester-enriched lipoprotein which under normal conditions is rapidly cleared by parenchymal liver cells. In this study the characteristics of the interaction of beta-VLDL with rat parenchymal cells, Hep G2 cells and human parenchymal cells are evaluated. The binding of beta-VLDL to these cells follows saturation kinetics (Bmax. respectively 117, 106 and 103 ng of beta-VLDL apoliprotein/mg of cell protein), with a relatively high affinity (Kd respectively for beta-VLDL of 10.7, 5.1 and 8.4 micrograms/ml). Competition studies of unlabelled beta-VLDL, low-density lipoprotein (LDL) or acetylated LDL with the binding of radiolabelled beta-VLDL indicate that a LDL-receptor-independent, Ca(2+)-independent, specific recognition site for beta-VLDL is present on rat and human parenchymal cells, whereas with Hep G2 cells or mouse macrophages beta-VLDL recognition is performed by the LDL receptor. The binding of beta-VLDL to Hep G2 cells was down-regulated by 89% by prolonged exposure to beta-VLDL, whereas for human parenchymal and rat parenchymal cells down-regulation of 44% and 20% respectively was observed. Studies with antibodies against the LDL receptor support the presence of a LDL-receptor-independent specific beta-VLDL recognition site on rat and human parenchymal cells. It is concluded that a LDL-receptor-independent recognition site for beta-VLDL is present on rat and human parenchymal liver cells. The presence of a LDL-receptor-independent recognition site on human parenchymal cells may mediate in vivo the uptake of beta-VLDL during consumption of a cholesterol-rich diet, when LDL receptors are down-regulated, thus protecting against the extrahepatic accumulation of the atherogenic beta-VLDL constituents. PMID:1311560

De Water, R; Kamps, J A; Van Dijk, M C; Hessels, E A; Kuiper, J; Kruijt, J K; Van Berkel, T J



Effect of oxidation on the structure of human low- and high-density lipoproteins.  


This work presents a controlled study of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) structural changes due to in vitro oxidation with copper ions. The changes were studied by small-angle x-ray scattering (SAXS) and dynamic light scattering (DLS) techniques in the case of LDL and by SAXS, DLS, and Z-scan (ZS) techniques in the case of HDL. SAXS data were analyzed with a to our knowledge new deconvolution method. This method provides the electron density profile of the samples directly from the intensity scattering of the monomers. Results show that LDL particles oxidized for 18 h show significant structural changes when compared to nonoxidized particles. Changes were observed in the electrical density profile, in size polydispersity, and in the degree of flexibility of the APO-B protein on the particle. HDL optical results obtained with the ZS technique showed a decrease of the amplitude of the nonlinear optical signal as a function of oxidation time. In contrast to LDL results reported in the literature, the HDL ZS signal does not lead to a complete loss of nonlinear optical signal after 18 h of copper oxidation. Also, the SAXS results did not indicate significant structural changes due to oxidation of HDL particles, and DLS results showed that a small number of oligomers formed in the sample oxidized for 18 h. All experimental results for the HDL samples indicate that this lipoprotein is more resistant to the oxidation process than are LDL particles. PMID:24940777

Oliveira, Cristiano L P; Santos, Priscila R; Monteiro, Andrea M; Figueiredo Neto, Antonio M



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

SciTech Connect

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

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



Structural investigation of reconstituted high density lipoproteins by scanning tunnelling microscopy  

NASA Astrophysics Data System (ADS)

Being able to participate in the reverse cholesterol transport (RCT), high density lipoproteins (HDL) are known to be anti-atherogenic. In order to understand such a process, it is thus essential to have a detailed knowledge of the structure and molecular organisation of HDL. Reconstituted nascent high density lipoproteins (r-HDL), consisting of synthetic phospholipids together with different apolipoproteins (apo A-I, A-IV and E), were thus analysed by scanning tunnelling microscopy (STM). Both shape and dimensions of the discoidal HDL particles measured by this technique were found in good agreement with the data available from the literature. The accuracy of the STM pictures presented in this paper enables for the first time the visualisation of the molecular organisation of such macromolecules. The arrangement of the protein as antiparallel helical segments, is consistent with the general mode of organisation of apolipoprotein/phospholipid discoidal particles previously reported.

Culot, C.; Durant, F.; Lazarescu, S.; Thiry, P. A.; Vanloo, B.; Rosseneu, M. Y.; Lins, L.; Brasseur, R.



Small Dense Low Density Lipoprotein Particles Are Associated with Poor Outcome after Angioplasty in Peripheral Artery Disease  

PubMed Central

Purpose In patients suffering from symptomatic peripheral artery disease (PAD), percutaneous revascularization is the treatment of choice. However, restenosis may occur in 10 to 60% in the first year depending on a variety of factors. Small dense low density lipoprotein (sdLDL) particles are associated with an increased risk for cardiovascular events, but their role in the process of restenosis is not known. We conducted a prospective study to analyze the association of sdLDL particles with the outcome of balloon angioplasty in PAD. The composite primary endpoint was defined as improved walking distance and absence of restenosis. Methods Patients with angiographically documented PAD of the lower extremities who were scheduled for lower limb revascularization were consecutively recruited for the study. At baseline and at three month follow-up triglyceride, total cholesterol, LDL size and subclasses and HDL cholesterol and ankle-brachial index (ABI) were measured. Three months after the intervention duplex sonography was performed to detect restenosis. Results Sixty-four patients (53% male) with a mean age of 68.6±9.9 years were included. The proportion of small- dense LDL particles (class III and IV) was significantly lower (33.1±11.0% vs. 39.4±12.1%, p?=?0.038) in patients who reached the primary end-point compared with those who did not. Patients with improved walking distance and without restenosis had a significantly higher LDL size at baseline (26.6±1.1 nm vs. 26.1±1.1 nm, p?=?0.046) and at follow-up (26.7±1.1 nm vs. 26.2±0.9 nm, p?=?0.044) than patients without improvement. Conclusions Small-dense LDL particles are associated with worse early outcome in patients undergoing percutaneous revascularization for symptomatic PAD. PMID:25265512

Mosimann, Kathrin; Husmann, Marc; Thalhammer, Christoph; Wilkinson, Ian; Berneis, Kaspar; Amann-Vesti, Beatrice R.



The Low-Density Lipoprotein Receptor-Related Protein Regulates Cancer Cell Survival and Metastasis Development  

Microsoft Academic Search

Low-density lipoprotein receptor-related protein-1 (LRP-1) is a multifunctional receptor involved in receptor-mediated endocytosis and cell signaling. In this study, we show that LRP-1 is abundantly expressed in severe combined immuno- deficient (SCID) mouse xenografts by various human cancer cell lines that express very low or undetectable levels of LRP-1 when cultured in 21% O2 in vitro (standard cell culture conditions).

Valerie Montel; Alban Gaultier; Robin D. Lester; W. Marie Campana; Steven L. Gonias



Antioxidation of human low density lipoprotein by unconjugated and conjugated bilirubins  

Microsoft Academic Search

We demonstrate here that both unconjugated bilirubin (Bu) and conjugated bilirubin (Bc) can protect human low density lipoprotein (LDL) against oxidation by oxyradicals generated by 2,2?-azo-bis(2-amidinopropane) dihydrochloride at 37°. The oxidation was assessed by agarose gel electrophoresis and was further corroborated by assaying the malondialdehydes and lipid peroxides formed throughout oxidation. On a per mole basis, Bu and less so

Tai-Wing Wu; K. P. Fung; Jun Wu; Chih-Chin Yang; Richard D. Weisel



Regulation of acetylated low density lipoprotein uptake in macrophages by pertussis toxin-sensitive G proteins  

Microsoft Academic Search

Class A scavenger receptors (SR-A) mediate the uptake of modified low density lipoprotein (LDL) by mac- rophages. Although not typically associated with the activa- tion of intracellular signaling cascades, results with perito- neal macrophages indicate that the SR-A ligand acetylated LDL (AcLDL) promotes activation of cytosolic kinases and phospholipases. These signaling responses were blocked by the treatment of cells with

Stewart C. Whitman; Alan Daugherty; Steven R. Post


A Gene for a Low Density Lipoprotein Receptor-Related Protein in the Nematode Caenorhabditis elegans  

Microsoft Academic Search

A >23-kb gene that encodes a large integral membrane protein with a predicted structure similar to that of the low density lipoprotein (LDL) receptor-related protein (LRP) of mammals has been isolated and sequenced from the free-living nematode Caenorhabditis elegans. The 4753-amino acid predicted C. elegans product shares a nearly identical number and arrangement of amino acid sequence motifs with human

John Yochem; Iva Greenwald



Studies of low density lipoprotein molecular weight in human beings with coronary artery disease  

Microsoft Academic Search

Low density lipoprotein molecular weight (LDL MW) correlates positively with coronary artery disease in cho- lesterol-fed nonhuman primates. To evaluate this in human beings with coronary artery disease (CAD) we measured LDL MW in 93 volunteers undergoing coronary angiography (47 controls and 46 CAD patients). LDL MW of CAD patients was less than that of controls (patients, 2.79 * 0.17

John R. Crouse; Johns S. Parks; Harry M. Schey; Frederic R. Kahl


Effect of temperature and phase transition on oxidation resistance of low density lipoprotein  

Microsoft Academic Search

The study of the effect of temperature on the kinetics of low density lipoprotein (LDL) oxidation was car- ried out by measuring the conjugated diene (CD) versus time curves at a fixed LDL concentration (0.1 pu) and at different Cu2' concentrations (0.5-10 p~) in a wide temperature range, from 10°C to 45°C. The core melting point of the LDL determined

Pilar Ramos; Steven Paul Gieseg; Bernhard Schuster; Hermann EsterbauerlY


Interactions of serum copper, selenium, and low density lipoprotein cholesterol in atherogenesis  

Microsoft Academic Search

OBJECTIVE--To investigate the interactions between serum copper, selenium, and low density lipoprotein cholesterol concentrations with regard to the progression of carotid atherosclerosis. DESIGN--Longitudinal study of a cohort of middle aged men followed up for 24 months. SETTING--Epidemiological survey of the population of seven communities in eastern Finland. SUBJECTS--126 men aged 42, 48, 54, or 60 at examination randomly selected from

J T Salonen; R Salonen; K Seppänen; M Kantola; S Suntioinen; H Korpela



Apolipoprotein AI charge and conformation regulate the clearance of reconstituted high density lipoprotein in vivo  

Microsoft Academic Search

While low apolipoprotein A-I (apoA-I) levels are primarily associated with increased high density lipoprotein (HDL) fractional catabolic rate (FCR), the factors that regu- late the clearance of HDL from the plasma are unclear. In this study, the effect of lipid composition of reconstituted HDL particles (LpA-I) on their rate of clearance from rab- bit plasma has been investigated. Sonicated LpA-I

Sylvie Braschi; Marie-Claude Vohl; Daniel L. Sparks


Absence of Monocyte Chemoattractant Protein1 Reduces Atherosclerosis in Low Density Lipoprotein Receptor–Deficient Mice  

Microsoft Academic Search

Recruitment of blood monocytes into the arterial subendothelium is one of the earliest steps in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine, is one likely signal involved in this process. To test MCP-1’s role in atherogenesis, low density lipoprotein (LDL) receptor–deficient mice were made genetically deficient for MCP-1 and fed a high cholesterol diet. Despite having the same amount

Long Gu; Yoshikatsu Okada; Steven K. Clinton; Craig Gerard; Galina K. Sukhova; Peter Libby; Barrett J. Rollins



Langmuir–Blodgett films of polyaniline for low density lipoprotein detection  

Microsoft Academic Search

Langmuir–Blodgett (LB) films of polyaniline (PANI) were utilized for the fabrication of impedimetric immunosensor for detection of human plasma low density lipoprotein (LDL) by immobilizing anti-apolipoprotein B (AAB) via EDC–NHS coupling. The modified electrodes were characterized by electrochemical impedance spectroscopy (EIS) and scanning electron microscopy. AAB\\/PANI–SA LB immunoelectrodes studied by EIS spectroscopy revealed detection of LDL in the wide range

Zimple Matharu; G. Sumana; Vinay Gupta; B. D. Malhotra



Effects of oxidative modification of cholesterol in isolated low density lipoproteins on cultured smooth muscle cells  

Microsoft Academic Search

It has been proposed that low density lipoprotein (LDL) must undergo oxidative modification before it can participate in atherosclerosis. The present paper studied the effect of cholesterol oxidation in LDL on cultured vascular smooth muscle cells. LDL was oxidized by cholesterol oxidase (3-ß-hydroxy-steroid oxidase) which catalyzes the oxidation of cholesterol to 4-cholesten-3 one and other oxidized cholesterol derivatives. Cholesterol oxidase

Kanzhi Liu; Bram Ramjiawan; Michael J. B. Kutryk; Grant N. Pierce



Resveratrol inhibits metal ion-dependent and independent peroxidation of porcine low-density lipoproteins  

Microsoft Academic Search

Resveratrol, a phytoalexin (3, 4?, 5, trihydroxystilbene) present in some red wines, has been reported to inhibit copper-mediated low-density lipoprotein (LDL) oxidation. In this study, we examined the efficiency of this compound in inhibiting metal ion-dependent and independent peroxidation of porcine LDL. At 0.5, 1, or 1.5 ?M, transresveratrol prolonged the lag time preceding the onset of conjugated diene formation

Leila Belguendouz; Lucie Fremont; Alain Linard



Dietary effects on oxidation of low-density lipoprotein and atherogenesis  

Microsoft Academic Search

Oxidization of low-density lipoprotein (LDL) particles leads to formation of atherosclerotic lesions and increased risk of\\u000a cardiovascular disease (CVD) via a complex cascade of biochemical events occurring mostly within the arterial wall. Multiple\\u000a dietary factors impact LDL oxidation levels, such as fat-rich meals, hyper- and hypocaloric diets, and specific nutrients\\u000a (vitamins E, C, and beta-carotene; mono- and polyunsaturated fatty acids;

Pietro Galassetti; Andria Pontello



Cardiovascular disease and nutrient antioxidants: Role of low?density lipoprotein oxidation  

Microsoft Academic Search

Increasing evidence indicates that oxidative modification of low?density lipoprotein (LDL) is causally related to atherosclerosis. Oxidatively modified LDL (oxLDL), in contrast to native LDL, is taken up avidly by macrophages, leading to formation of lipid?laden foam cells. Foam cells are pathognomonic of the atherosclerotic fatty streak. Modified LDL may also promote atherosclerosis by many other mechanisms, such as recruitment and

Balz Frei



Characterization of native and oxidized human low-density lipoproteins by the Z-scan technique  

Microsoft Academic Search

The nonlinear optical response of human normal and oxidized by Cu2+ low-density lipoproteins particles (LDL), were investigated by the Z-scan technique as a function of temperature and concentration of LDL particles. The Z-scan signals increase linearly with concentration of normal LDL particles, following the usual Beer–Lambert law in a broad range of concentrations. The oxidized LDL particles do not show

S. L. Gómez; R. F. Turchiello; M. C. Jurado; P. Boschcov; M. Gidlund; A. M. Figueiredo Neto



Association of Apolipoprotein A Phenotypes and Oxidized Low-Density Lipoprotein Immune Complexes in Children  

Microsoft Academic Search

Background: SmallapolipoproteinA(apo(A))phenotypes and oxidized low-density lipoprotein immune complexes (oxLDL-ICs) are known to be associated with the develop- ment of atherosclerosis in adults. Presence of these factors in children and their relationships with other known car- diovascular risk factors have not been well documented. Objective: To examine the relationship of oxLDL-ICs with apo(A) phenotypes and other known cardiovascu- lar risk factors

Ilyas Kamboh; Maria Lopes-Virella; Frank Treiber; Gerry Hobbs



Down-regulationof the low-density lipoprotein receptor by dietary cholesterol1  

Microsoft Academic Search

To determine the effect of dietary cholesterol on the low-density lipoprotein (LDL) receptor of circulating mononuclear cells, nine adults (six men, three women) consumed a natural diet consisting of 45% of the calories as carbohydrate, 40% as fat, and 15% as protein, polyunsaturated\\/saturated fatty acid ratio 0.80 to 0.84, and either 137 ± 25 mg cholesterol per day (low cholesterol

Deborah Applebaum-Bowden; Steven M Haffner; Elaine Harisook; K Helen Luk; John JAlbers; William R Hazzard



Relation of high-density lipoprotein cholesterol concentration to type of diabetes and its control  

Microsoft Academic Search

Serum cholesterol and high-density lipoprotein (HDL) cholesterol concentrations were measured in 192 diabetics (94 with juvenile-onset and 98 with maturity-onset diabetes) and 177 non-diabetic controls. Hb A1C, an index of blood sugar control, was also measured in the diabetics. Serum cholesterol concentrations were similar in all the diabetics and controls, but HDL cholesterol concentrations were lower in patients with maturity-onset

A L Kennedy; T R Lappin; T D Lavery; D R Hadden; J A Weaver; D A Montgomery



Elevated Uptake of Low Density Lipoproteins by Human Lung Cancer Tissue in Vivo1  

Microsoft Academic Search

In order to explore new treatment modalities for cancer, it is impor tant to identify qualitative or quantitative differences in metabolic pro cesses between normal and malignant cells. Previous in vitro and in vivo studies have shown that acute myelogenous leukemia cells have elevated receptor-mediated uptake of low density lipoproteins (LDL), compared to normal VVBC.High receptor-mediated uptake of LDL by

Sigurd Vitols; Curt Peterson; Olle Larsson; Peter Holm



Tomato lycopene and low density lipoprotein oxidation: A human dietary intervention study  

Microsoft Academic Search

Increase in low density lipoprotein (LDL) oxidation is hypothesized to be causally associated with increasing risk of atherosclerosis\\u000a and coronary heart disease. In recent epidemiological studies, tissue and serum levels of lycopene, a carotenoid available\\u000a from tomatoes, have been found to be inversely related to risk of coronary heart disease. A study was undertaken to investigate\\u000a the effect of dietary

Sanjiv Agarwal; A. Venketeshwer Rao



Formation of F 2-isoprostanes in oxidized low density lipoprotein: Inhibitory effect of hydroxytyrosol  

Microsoft Academic Search

Oxidatively-modified low-density lipoproteins (LDL) contribute to the onset of the atherosclerotic disease. A recently discovered marker of lipid peroxidation is a series of prostaglandin F2-like compounds, the prostaglandin isomers isoprostanes, that are generated from arachidonic acid through cyclooxygenase-independent pathways following free radical injury and are endowed with potent biological activities. The incidence of cardiovascular disease in the Mediterranean area is

Marco Salami; Claudio Galli; Leonardo De Angelis; Francesco Visioli



Dipicolinic acid prevents the copper-dependent oxidation of low density lipoprotein  

Microsoft Academic Search

Effect of dipicolinic acid (pyridine 2,6-dicarboxylic acid) and pyridine compounds on the copper-dependent oxidation of human low density lipoprotein was analyzed in relation to the inhibition of copper reduction. Dipicolinic acid inhibited copper-dependent LDL oxidation completely, but the LDL oxidation was slightly inhibited by pyridine compounds with one carboxyl group at 2 or 6-position. Reduction of copper by LDL itself

Keiko Murakami; Yasuko Tanemura; Masataka Yoshino



High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1  

PubMed Central

Oxidized sterols consumed in the diet or formed on low-density lipoprotein (LDL) are toxic to endothelial cells and macrophages and are thought to have a central role in promoting atherogenesis. The ATP-binding cassette transporter ABCG1 was recently shown to promote efflux of cholesterol from macrophages to high-denisty lipoprotein (HDL). We show that HDL protects macrophages from apoptosis induced by loading with free cholesterol or oxidized LDL. The protective effect of HDL was reduced in Abcg1?/? macrophages, especially after loading with oxidized LDL. Similarly, HDL exerted a protective effect against apoptosis induced by 7-ketocholesterol, the major oxysterol present in oxidized LDL and atherosclerotic lesions, in Abcg1+/+, but not in Abcg1?/? macrophages. In transfected 293 cells, efflux of 7-ketocholesterol and related oxysterols was completely dependent on expression of ABCG1 and the presence of HDL in media. In contrast, ABCA1 and apoA-1 did not stimulate the efflux of 7-ketocholesterol into media. HDL stimulated the efflux of 7-ketocholesterol from Abcg1+/+, but not from Abcg1?/? macrophages. In Abcg1?/? mice fed a high-cholesterol diet, plasma levels of 7-ketocholesterol were reduced, whereas their macrophages accumulated 7-ketocholesterol. These findings indicate a specific role for ABCG1 in promoting efflux of 7-ketocholesterol and related oxysterols from macrophages onto HDL and in protecting these cells from oxysterol-induced cytotoxicity. PMID:17846428

Terasaka, Naoki; Wang, Nan; Yvan-Charvet, Laurent; Tall, Alan R.



High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1.  


Oxidized sterols consumed in the diet or formed on low-density lipoprotein (LDL) are toxic to endothelial cells and macrophages and are thought to have a central role in promoting atherogenesis. The ATP-binding cassette transporter ABCG1 was recently shown to promote efflux of cholesterol from macrophages to high-denisty lipoprotein (HDL). We show that HDL protects macrophages from apoptosis induced by loading with free cholesterol or oxidized LDL. The protective effect of HDL was reduced in Abcg1(-/-) macrophages, especially after loading with oxidized LDL. Similarly, HDL exerted a protective effect against apoptosis induced by 7-ketocholesterol, the major oxysterol present in oxidized LDL and atherosclerotic lesions, in Abcg1(+/+), but not in Abcg1(-/-) macrophages. In transfected 293 cells, efflux of 7-ketocholesterol and related oxysterols was completely dependent on expression of ABCG1 and the presence of HDL in media. In contrast, ABCA1 and apoA-1 did not stimulate the efflux of 7-ketocholesterol into media. HDL stimulated the efflux of 7-ketocholesterol from Abcg1(+/+), but not from Abcg1(-/-) macrophages. In Abcg1(-/-) mice fed a high-cholesterol diet, plasma levels of 7-ketocholesterol were reduced, whereas their macrophages accumulated 7-ketocholesterol. These findings indicate a specific role for ABCG1 in promoting efflux of 7-ketocholesterol and related oxysterols from macrophages onto HDL and in protecting these cells from oxysterol-induced cytotoxicity. PMID:17846428

Terasaka, Naoki; Wang, Nan; Yvan-Charvet, Laurent; Tall, Alan R



Estimation oftheConcentration of Low-Density Lipoprotein Cholesterol inPlasma, Without UseofthePreparative Ultracentrifuge  

Microsoft Academic Search

A method for estimating the cholesterol content of the serum low-density lipoprotein fraction (Sf- 0.20)is presented. The method involves measure- ments of fasting plasma total cholesterol, tri- glyceride, and high-density lipoprotein cholesterol concentrations, none of which requires the use of the preparative ultracentrifuge. Cornparison of this suggested procedure with the more direct procedure, in which the ultracentrifuge is used, yielded

William T. Friedewald; Robert I. Levy; Donald S. Fredrickson



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

PubMed Central

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

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



Kinetics of incorporation/redistribution of photosensitizer hypericin to/from high-density lipoproteins.  


By means of fluorescence spectroscopy we have studied the kinetics of interaction of a photosensitizer hypericin (Hyp) with high-density lipoproteins (HDL). Hyp is incorporated into HDL molecules as monomer till ratio Hyp/HDL ?8:1 and above this ratio forms non-fluorescent aggregates. This number is different from that found in the case of Hyp incorporation into low-density lipoprotein (LDL) molecules (8:1 vs 30:1). The difference is mainly attributed to the smaller size of HDL in comparison with LDL molecule. Biphasic kinetics of Hyp association with HDL was observed. The rapid phase of incorporation is completed within seconds, while the slow one lasts several minutes. The kinetics of the association of Hyp molecules with free HDL, Hyp/HDL=10:1 complex and the redistribution of Hyp from Hyp/HDL=70:1 complex to free HDL molecules reveal a qualitative similar characteristics of these processes with those observed for the interaction of Hyp with LDL. However, the incorporation of Hyp into HDL in the "slow" phase is more rapid than to LDL and extend of Hyp penetration into lipoproteins in the fast phase is also much higher in the case of HDL. The lower concentration of cholesterol molecules in outer shell of HDL particles is probably the determining factor for the more rapid kinetics of Hyp incorporation to and redistribution from these molecules when comparing with LDL particles. PMID:25238911

Joniova, Jaroslava; Buriankova, Luboslava; Buzova, Diana; Miskovsky, Pavol; Jancura, Daniel



[The difference of conformation of apoB-100 in lipoproteins of low and very low density. The modified lipoproteins and destructive inflammation in intima of arteries: a lecture].  


The formation of ligand occurs in phylogenetically earlier lipoproteins of very low density and later lipoproteins of very low density when apoB- 100 takes active conformation in association with essential polyenoic fatty acids, in form of ethers with alcohol cholesterol, palmitic and oleic triglycerides. In lipoproteins of low density apoB-100-domain-ligand is formed, in lipoproteins of very low density apoE/B-100-ligand is formed. The ligand lipoproteins absorb cells using apoE/B-100 and apoB-100 receptor endocytosis. In cases of excess of palmitic triglycerides. and lipoproteins of very low density of the same name in blood, damage of primary structure of post-heparin, hepatic lipoprotein lipase and co-enzymes apoC-II and apoC-II, phenotype E2/E2 blood accumulates pre-ligand lipoproteins rich in triglycerides. In case of pathology of apoB-100-receptor post-ligand lipoproteins of low density with low content of triglycerides are cumulated. All non-ligand lipoproteins in a physiological way denature neutrophils. The presence of pathology induces modification in case of action of other agents (glyco-toxins). The pre-lipoproteins form in the intima of arteries soft voluminous plaques and such destructive inflammatory process as athero-thrombosis. The post-lipoproteins form flat plaques and destructive inflammatory atheromatosis. The atherosclerosis can be labeled as disease ofconformation. The surplus of palmitic saturated fatty acids in food, phenotype E2/E2 and deletion of gene apoB-100-receptor are causes of intima lesion. The non-ligand lipoproteins form destructive process, dying foam cells and macrophages--inflammatory component. The atheromatosis is a result of realization of biological function of endoecology, support of "purity" of intercellular medium. PMID:25069231

Titov, V N; Ameliyushkina, V A; Kotkina, T I; Aripovskiy, A V



A novel chromatographic method for the preparation of high density lipoproteins.  


High density lipoproteins (HDL) were isolated by a procedure employing polyanion precipitation and column chromatography. The product polyanion precipitation and column chromatography. The product was free of low denisty lipoproteins (LDL) but serum albumin (HSA) was still present. The remaining HSA was removed by an immunoadsorbent column. The HDL isolated by our method was compared to another HDL preparation isolated from the same plasma sample by the combination of ultracentrifugation and gel chromatgraphy. It was found to have approximately the same lipid and protein composition as the HDL isolated by conventional techniques. Minor differences included a higher phospholipid and apoprotein E content and lower triglyceride and ApoC II content of the HDL isolated by column chromatography. The method described here is considerably less tedious than earlier techniques, can be scaled up without substantial increase in labor and results in an approximately 30% higher yield than the method described by Rudel et al. PMID:6997859

Jahani, M; Huttash, R G; Lacko, A G



The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?  

PubMed Central

There is unequivocal evidence of an inverse association between plasma high-density lipoprotein (HDL) cholesterol concentrations and the risk of cardiovascular disease, a finding that has led to the hypothesis that HDL protects from atherosclerosis. This review details the experimental evidence for this “HDL hypothesis”. In vitro studies suggest that HDL has a wide range of anti-atherogenic properties but validation of these functions in humans is absent to date. A significant number of animal studies and clinical trials support an atheroprotective role for HDL; however, most of these findings were obtained in the context of marked changes in other plasma lipids. Finally, genetic studies in humans have not provided convincing evidence that HDL genes modulate cardiovascular risk. Thus, despite a wealth of information on this intriguing lipoprotein, future research remains essential to prove the HDL hypothesis correct. PMID:20371550

Vergeer, Menno; Holleboom, Adriaan G.; Kastelein, John J. P.; Kuivenhoven, Jan Albert



Ascorbic acid protects lipids in human plasma and low-density lipoprotein against oxidative damage  

SciTech Connect

The authors exposed human blood plasma and low-density lipoprotein (LDL) to many different oxidative challenges and followed the temporal consumption of endogenous antioxidants in relation to the initiation of oxidative damage. Under all types of oxidizing conditions, ascorbic acid completely protects lipids in plasma and LDL against detectable peroxidative damage as assessed by a specific and highly sensitive assay for lipid peroxidation. Ascorbic acid proved to be superior to the other water-soluble plasma antioxidants bilirubin, uric acid, and protein thiols as well as to the lipoprotein-associated antioxidants alpha-tocopherol, ubiquinol-10, lycopene, and beta-carotene. Although these antioxidants can lower the rate of detectable lipid peroxidation, they are not able to prevent its initiation. Only ascorbic acid is reactive enough to effectively intercept oxidants in the aqueous phase before they can attack and cause detectable oxidative damage to lipids.

Frei, B. (Department of Nutrition, Harvard School of Public Health, Boston, MA (Unites States))



Novel physiological function of sphingomyelin in plasma. Inhibition of lipid peroxidation in low density lipoproteins.  


Although sphingomyelin (SPH) is a major constituent of all lipoproteins, its physiological function in plasma is not known. In this study, we tested the hypothesis that SPH inhibits lipid peroxidation in low density lipoproteins (LDL) because of its effects on surface fluidity and packing density and that the relative resistance of the buoyant LDL to oxidation, compared with the dense LDL, is partly due to their higher SPH content. Depletion of SPH by treatment with SPHase resulted in shortened lag times and increased rates of oxidation in both LDL subfractions, as measured by the conjugated diene formation in the presence of Cu(2+). Oxidation of LDL by soybean lipoxygenase was similarly stimulated by the degradation of SPH. Oxidation-induced fluorescence decay of diphenylhexatriene-labeled phosphatidylcholine (PC), equilibrated with LDL-PC, was accelerated significantly by the enzymatic depletion of SPH from the lipoprotein. Oxidation of 16:0-18:2 PC in the proteoliposomes was inhibited progressively by the incorporation of increasing amounts of egg SPH into the liposomes. Treatment of SPH-containing proteoliposomes with SPHase reversed the effect of SPH, showing that the presence of intact SPH is necessary for the inhibition of oxidation. Although the incorporation of SPH into the same liposome as the PC (intrinsic SPH) protected the PC against oxidation, the addition of SPH liposomes to PC liposomes (extrinsic SPH) was not effective. Oxidation of 16:0-18:2 PC in liposomes was also inhibited by the incorporation of dipalmitoyl-PC, but not by free cholesterol. These results suggest that SPH acts as a physiological inhibitor of lipoprotein oxidation, possibly by modifying the fluidity of the phospholipid monolayer and thereby inhibiting the lateral propagation of the lipid peroxy radicals. PMID:10593936

Subbaiah, P V; Subramanian, V S; Wang, K



Salutary Effects of Hemodialysis on Low-Density Lipoprotein Proinflammatory and High-Density Lipoprotein Anti-inflammatory Properties in Patient With End-Stage Renal Disease  

PubMed Central

End-stage renal disease (ESRD) causes oxidative stress, inflammation, low-density lipoprotein (LDL) oxidation, high-density lipoprotein (HDL) deficiency and accelerated atherosclerosis. Uptake of oxidized LDL by macrophages results in foam cell and plaque formation. HDL mitigates atherosclerosis via reverse cholesterol transport and inhibition of LDL oxidation. ESRD heightens LDL inflammatory activity and suppresses HDL anti-inflammatory activity. The effect of hemodialysis on the LDL and HDL inflammatory properties is unknown. By removing the potential pro-oxidant/proinflammatory uremic toxins, dialysis may attenuate LDL inflammatory and HDL anti-inflammatory properties. Conversely, exposure to dialyzer membrane and tubing and influx of impurities from dialysate can intensify LDL and HDL inflammatory activities. This study examined the effect of hemodialysis on LDL and HDL inflammatory activities. Plasma samples were obtained from 12 normal control and 26 ESRD patients before and after hemodialysis with (16 patients) or without (10 patients) heparinization. HDL and LDL were isolated and tested for monocyte chemotactic activity in cultured endothelial cells. ESRD patients had increased LDL chemotactic activity, reduced HDL anti-inflammatory activity, paraoxonase and glutathione peroxidase levels, and elevated plasma IL-6 before dialysis. Hemodialysis partially improved LDL inflammatory and HDL anti-inflammatory activities and enhanced patients’ HDL ability to suppress their LDL inflammatory activity. The salutary effect on LDL inflammatory activity was significantly greater in patients dialyzed with than those without heparin. ESRD heightens LDL inflammatory and impairs HDL anti-inflammatory activities. Hemodialysis partially improves LDL and HDL inflammatory activities. The salutary effects of hemodialysis are in part mediated by heparin, which is known to possess lipolytic and antioxidant properties. PMID:21830637

Vaziri, Nosratola D.; Navab, Kaveh; Gollapudi, Pavan; Moradi, Hamid; Pahl, Madeleine V.; Barton, Cyril H.; Fogelman, Alan M.; Navab, Mohamad



Salutary effects of hemodialysis on low-density lipoprotein proinflammatory and high-density lipoprotein anti-inflammatory properties in patient with end-stage renal disease.  


End-stage renal disease (ESRD) causes oxidative stress, inflammation, low-density lipoprotein (LDL) oxidation, high-density lipoprotein (HDL) deficiency and accelerated atherosclerosis. Uptake of oxidized LDL by macrophages results in foam cell and plaque formation. HDL mitigates atherosclerosis via reverse cholesterol transport and inhibition of LDL oxidation. ESRD heightens LDL inflammatory activity and suppresses HDL anti-inflammatory activity. The effect of hemodialysis on the LDL and HDL inflammatory properties is unknown. By removing the potential pro-oxidant/proinflammatory uremic toxins, dialysis may attenuate LDL inflammatory and HDL anti-inflammatory properties. Conversely, exposure to dialyzer membrane and tubing and influx of impurities from dialysate can intensify LDL and HDL inflammatory activities. This study examined the effect of hemodialysis on LDL and HDL inflammatory activities. Plasma samples were obtained from 12 normal control and 26 ESRD patients before and after hemodialysis with (16 patients) or without (10 patients) heparinization. HDL and LDL were isolated and tested for monocyte chemotactic activity in cultured endothelial cells. ESRD patients had increased LDL chemotactic activity, reduced HDL anti-inflammatory activity, paraoxonase and glutathione peroxidase levels, and elevated plasma IL-6 before dialysis. Hemodialysis partially improved LDL inflammatory and HDL anti-inflammatory activities and enhanced patients' HDL ability to suppress their LDL inflammatory activity. The salutary effect on LDL inflammatory activity was significantly greater in patients dialyzed with than those without heparin. ESRD heightens LDL inflammatory and impairs HDL anti-inflammatory activities. Hemodialysis partially improves LDL and HDL inflammatory activities. The salutary effects of hemodialysis are in part mediated by heparin, which is known to possess lipolytic and antioxidant properties. PMID:21830637

Vaziri, Nosratola D; Navab, Kaveh; Gollapudi, Pavan; Moradi, Hamid; Pahl, Madeleine V; Barton, Cyril H; Fogelman, Alan M; Navab, Mohamad



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


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

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



Low-Density Lipoprotein Modified by Myeloperoxidase in Inflammatory Pathways and Clinical Studies  

PubMed Central

Oxidation of low-density lipoprotein (LDL) has a key role in atherogenesis. Among the different models of oxidation that have been studied, the one using myeloperoxidase (MPO) is thought to be more physiopathologically relevant. Apolipoprotein B-100 is the unique protein of LDL and is the major target of MPO. Furthermore, MPO rapidly adsorbs at the surface of LDL, promoting oxidation of amino acid residues and formation of oxidized lipoproteins that are commonly named Mox-LDL. The latter is not recognized by the LDL receptor and is accumulated by macrophages. In the context of atherogenesis, Mox-LDL accumulates in macrophages leading to foam cell formation. Furthermore, Mox-LDL seems to have specific effects and triggers inflammation. Indeed, those oxidized lipoproteins activate endothelial cells and monocytes/macrophages and induce proinflammatory molecules such as TNF? and IL-8. Mox-LDL may also inhibit fibrinolysis mediated via endothelial cells and consecutively increase the risk of thrombus formation. Finally, Mox-LDL has been involved in the physiopathology of several diseases linked to atherosclerosis such as kidney failure and consequent hemodialysis therapy, erectile dysfunction, and sleep restriction. All these issues show that the investigations of MPO-dependent LDL oxidation are of importance to better understand the inflammatory context of atherosclerosis. PMID:23983406

Vanhamme, Luc; Roumeguere, Thierry; Zouaoui Boudjeltia, Karim



Analysis of drug interactions with very low density lipoprotein by high-performance affinity chromatography.  


High-performance affinity chromatography (HPAC) was utilized to examine the binding of very low density lipoprotein (VLDL) with drugs, using R/S-propranolol as a model. These studies indicated that two mechanisms existed for the binding of R- and S-propranolol with VLDL. The first mechanism involved non-saturable partitioning of these drugs with VLDL, which probably occurred with the lipoprotein's non-polar core. This partitioning was described by overall affinity constants of 1.2 (±0.3)?×?10(6) M(-1) for R-propranolol and 2.4 (±0.6)?×?10(6) M(-1) for S-propranolol at pH 7.4 and 37 °C. The second mechanism occurred through saturable binding by these drugs at fixed sites on VLDL, such as represented by apolipoproteins on the surface of the lipoprotein. The association equilibrium constants for this saturable binding at 37 °C were 7.0 (±2.3)?×?10(4) M(-1) for R-propranolol and 9.6 (±2.2)?×?10(4) M(-1) for S-propranolol. Comparable results were obtained at 20 and 27 °C for the propranolol enantiomers. This work provided fundamental information on the processes involved in the binding of R- and S-propranolol to VLDL, while also illustrating how HPAC can be used to evaluate relatively complex interactions between agents such as VLDL and drugs or other solutes. PMID:25103529

Sobansky, Matthew R; Hage, David S



Lipoprotein Lipase and PPAR Alpha Gene Polymorphisms, Increased Very-Low-Density Lipoprotein Levels, and Decreased High-Density Lipoprotein Levels as Risk Markers for the Development of Visceral Leishmaniasis by Leishmania infantum.  


In visceral leishmaniasis (VL) endemic areas, a minority of infected individuals progress to disease since most of them develop protective immunity. Therefore, we investigated the risk markers of VL within nonimmune sector. Analyzing infected symptomatic and, asymptomatic, and noninfected individuals, VL patients presented with reduced high-density lipoprotein cholesterol (HDL-C), elevated triacylglycerol (TAG), and elevated very-low-density lipoprotein cholesterol (VLDL-C) levels. A polymorphism analysis of the lipoprotein lipase (LPL) gene using HindIII restriction digestion (N = 156 samples) (H+ = the presence and H- = the absence of mutation) revealed an increased adjusted odds ratio (OR) of VL versus noninfected individuals when the H+/H+ was compared with the H-/H- genotype (OR = 21.3; 95% CI = 2.32-3335.3; P = 0.003). The H+/H+ genotype and the H+ allele were associated with elevated VLDL-C and TAG levels (P < 0.05) and reduced HDL-C levels (P < 0.05). An analysis of the L162V polymorphism in the peroxisome proliferator-activated receptor alpha (PPAR?) gene (n = 248) revealed an increased adjusted OR when the Leu/Val was compared with the Leu/Leu genotype (OR = 8.77; 95% CI = 1.41-78.70; P = 0.014). High TAG (P = 0.021) and VLDL-C (P = 0.023) levels were associated with susceptibility to VL, whereas low HDL (P = 0.006) levels with resistance to infection. The mutated LPL and the PPAR? Leu/Val genotypes may be considered risk markers for the development of VL. PMID:25242866

Carvalho, Márcia Dias Teixeira; Alonso, Diego Peres; Vendrame, Célia Maria Vieira; Costa, Dorcas Lamounier; Costa, Carlos Henrique Nery; Werneck, Guilherme Loureiro; Ribolla, Paulo Eduardo Martins; Goto, Hiro



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

PubMed Central

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

Martinez-Beamonte, Roberto; Navarro, Maria A.; Acin, Sergio; Guillen, Natalia; Barranquero, Cristina; Arnal, Carmen; Surra, Joaquin; Osada, Jesus



Influence of contraceptive pill and menstrual cycle on serum lipids and high-density lipoprotein cholesterol concentrations  

Microsoft Academic Search

The fluctuations of serum lipid and lipoprotein concentrations within one cycle were studied both in women using and not using oral contraceptives. High-density lipoprotein cholesterol decreased significantly from 1.47 mmol\\/l (57 mg\\/100 ml) to 1.30 mmol\\/l (50 mg\\/100 ml) during one contraceptive cycle in eight women and rose again to the initial value during the pill-free days. The mean concentration

P N Demacker; R W Schade; A F Stalenhoef; P M Stuyt; A van't Laar



Assembly of very low density lipoproteins in rat liver: a study of nascent particles recovered from the rough endoplasmic reticulum  

Microsoft Academic Search

To investigate the assembly pathway for hepatic very low density lipoproteins (VLDL), nascent lipoproteins were recovered from a purified, intact rough endoplasmic reticulum (ER) fraction isolated from rat liver. Two fractions were re- covered by ultracentrifugation. Particles isolated at d 1.006 g\\/ml were triglyceride-rich particles containing apolipoprotein (apo)B-100 or apoB-48, and apoE with very small amounts of apoA-I. Compared with

Larry L. Swift


High density lipoproteins and type 2 diabetes: Emerging concepts in their relationship  

PubMed Central

Patients with type 2 diabetes mellitus (T2DM) frequently exhibit macrovascular complications of atherosclerotic cardiovascular (CV) disease. High density lipoproteins (HDL) are protective against atherosclerosis. Low levels of HDL cholesterol (HDL-C) independently contribute to CV risk. Patients with T2DM not only exhibit low HDL-C, but also dysfunctional HDL. Furthermore, low concentration of HDL may increase the risk for the development of T2DM through a decreased ? cell survival and secretory function. In this paper, we discuss emerging concepts in the relationship of T2DM with HDL. PMID:24977116

Kostapanos, Michael S; Elisaf, Moses S



Effects of fluvastatin therapy on lipids, antioxidants, oxidation of low density lipoproteins and trace metals  

Microsoft Academic Search

Objective: Oxidation of low density lipoproteins (LDL) is thought to be an important step in the development of atherosclerosis. Trace\\u000a metals are involved in oxidative processes. It was of interest to determine whether lipid-lowering therapy with fluvastatin,\\u000a a potent HMGCoA reductase inhibitor, affected LDL oxidation and trace metal levels.\\u000a \\u000a \\u000a \\u000a Methods: Twenty hypercholesterolemic patients were treated with fluvastatin (40?mg twice daily)

W. Leonhardt; T. Kurktschiev; D. Meissner; P. Lattke; C. Abletshauser; G. Weidinger; W. Jaross; M. Hanefeld



Different reactivities of high density lipoprotein2 subfractions with hepatic lipase  

Microsoft Academic Search

Human high density lipoproteins, (HDL,) consist of particles that contain both apolipoprotein (apo) A-I and apoA-I1 (A-I\\/A-II-HDLz) and others that contain apoA-I but are devoid of apoA-I1 (A-I-HDL,). When postprandial lipemia is pro- nounced, a fraction of HDL2 is converted into HDL3-like parti- cles. These HDL3 exhibit lower apoA-I\\/apoA-I1 ratios than the parent HDL,, suggesting preferential conversion of A-l\\/A-11- HDL,

Louis C. Smith; Antonio M. Gotto; Josef R. Patsch


Effects of diet and high density lipoprotein subfractions on the removal of cellular cholesterol  

Microsoft Academic Search

The effects of isocaloric substitutions of dietary polyunsaturated and saturated fat on the composition and function of plasma\\u000a high density lipoproteins (HDLs) were studied in 3 normal subjects who were fed saturate-rich and polyunsaturate-rich diet\\u000a programs. Compared to the saturated diets (P\\/S=0.4), polyunsaturated fat diets (P\\/S=4 or 2) reduced both plasma cholesterol\\u000a and triglyceride levels. In 2 of the subjects,

Richard L. Jackson; Charles J. Glueck; Satya N. Mathur; Arthur A. Spector



Lipoprotein lipase-mediated selective uptake from low density lipoprotein requires cell surface proteoglycans and is independent of scavenger receptor class B type 1.  


Lipoprotein lipase (LpL) hydrolyzes chylomicron and very low density lipoprotein triglycerides to provide fatty acids to tissues. Aside from its lipolytic activity, LpL promotes lipoprotein uptake by increasing the association of these particles with cell surfaces allowing for the internalization by receptors and proteoglycans. Recent studies also indicate that LpL stimulates selective uptake of lipids from high density lipoprotein (HDL) and very low density lipoprotein. To study whether LpL can mediate selective uptake of lipids from low density lipoprotein (LDL), LpL was incubated with LDL receptor negative fibroblasts, and the uptake of LDL protein, labeled with (125)I, and cholesteryl esters traced with [(3)H]cholesteryl oleoyl ether, was compared. LpL mediated greater uptake of [(3)H]cholesteryl oleoyl ether than (125)I-LDL protein, a result that indicated selective lipid uptake. Lipid enrichment of cells was confirmed by measuring cellular cholesterol mass. LpL-mediated LDL selective uptake was not affected by the LpL inhibitor tetrahydrolipstatin but was nearly abolished by heparin, monoclonal anti-LpL antibodies, or chlorate treatment of cells and was not found using proteoglycan-deficient Chinese hamster ovary cells. Selective uptake from HDL, but not LDL, was 2-3-fold greater in scavenger receptor class B type I overexpressing cells (SR-BI cells) than compared control cells. LpL, however, induced similar increases in selective uptake from LDL and HDL in either control or SR-BI cells, indicative of the SR-BI-independent pathway. This was further supported by ability of LpL to promote selective uptake from LDL in human embryonal kidney 293 cells, cells that do not express SR-BI. In Chinese hamster ovary cell lines that overexpress LpL, we also found that selective uptake from LDL was induced by both endogenous and exogenous LpL. Transgenic mice that overexpress human LpL via a muscle creatine kinase promoter had more LDL selective uptake in muscle than did wild type mice. In summary LpL stimulates selective uptake of cholesteryl esters from LDL via pathways that are distinct from SR-BI. Moreover this process also occurs in vivo in tissues where abundant LpL is present. PMID:10896681

Seo, T; Al-Haideri, M; Treskova, E; Worgall, T S; Kako, Y; Goldberg, I J; Deckelbaum, R J



Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation.  


Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted protein that binds to the epidermal growth factor-like-A domain of the low density lipoprotein receptor (LDLR) and mediates LDLR degradation in liver. Gain-of-function mutations in PCSK9 are associated with autosomal dominant hypercholesterolemia in humans. Size-exclusion chromatography of human plasma has shown PCSK9 to be partly associated with undefined high molecular weight complexes within the LDL size range. We used density gradient centrifugation to isolate LDL in plasma pooled from 5 normolipidemic subjects and report that >40% of total PCSK9 was associated with LDL. Binding of fluorophore-labeled recombinant PCSK9 to isolated LDL in vitro was saturable with a K(D) ? 325 nM. This interaction was competed >95% by excess unlabeled PCSK9, and competition binding curves were consistent with a one-site binding model. An N-terminal region of the PCSK9 prodomain (amino acids 31-52) was required for binding to LDL in vitro. LDL dose-dependently inhibited binding and degradation of cell surface LDLRs by exogenous PCSK9 in HuH7 cells. LDL also inhibited PCSK9 binding to mutant LDLRs defective at binding LDL. These data suggest that association of PCSK9 with LDL particles in plasma lowers the ability of PCSK9 to bind to cell surface LDLRs, thereby blunting PCSK9-mediated LDLR degradation. PMID:23400816

Kosenko, Tanja; Golder, Mia; Leblond, Geoffrey; Weng, Willy; Lagace, Thomas A



Effects of Statins on High-Density Lipoproteins: A Potential Contribution to Cardiovascular Benefit  

PubMed Central

Purpose The objective was to systematically review clinical trial data on the effects of statins on high-density lipoproteins (HDL) and to examine the possibility that this provides cardiovascular benefits in addition to those derived from reductions in low-density lipoproteins (LDL). Methods The PubMed database was searched for publications describing clinical trials of atorvastatin, pravastatin, rosuvastatin, and simvastatin. On the basis of predefined criteria, 103 were selected for review. Results Compared with placebo, statins raise HDL, measured as HDL-cholesterol (HDL-C) and apolipoprotein A-I (apo A-I); these elevations are maintained in the long-term. In hypercholesterolemia, HDL-C is raised by approximately 4% to 10%. The percentage changes are greater in patients with low baseline levels, including those with the common combination of high triglycerides (TG) and low HDL-C. These effects do not appear to be dose-related although there is evidence that, with the exception of atorvastatin, the changes in HDL-C are proportional to reductions in apo B-containing lipoproteins. The most likely explanation is a reduced rate of cholesteryl ester transfer protein (CETP)-mediated flow of cholesterol from HDL. There is some evidence that the statin effects on HDL reduce progression of atherosclerosis and risk of cardiovascular disease independently of reductions in LDL. Conclusion Statins cause modest increases in HDL-C and apo A-I probably mediated by reductions in CETP activity. It is plausible that such changes independently contribute to the cardiovascular benefits of the statin class but more studies are needed to further explore this possibility. PMID:18553127

Jones, Peter



Receptor-mediated uptake of low density lipoprotein stimulates bile acid synthesis by cultured rat hepatocytes  

SciTech Connect

The cellular mechanisms responsible for the lipoprotein-mediated stimulation of bile acid synthesis in cultured rat hepatocytes were investigated. Adding 280 micrograms/ml of cholesterol in the form of human or rat low density lipoprotein (LDL) to the culture medium increased bile acid synthesis by 1.8- and 1.6-fold, respectively. As a result of the uptake of LDL, the synthesis of (14C)cholesterol from (2-14C)acetate was decreased and cellular cholesteryl ester mass was increased. Further studies demonstrated that rat apoE-free LDL and apoE-rich high density lipoprotein (HDL) both stimulated bile acid synthesis 1.5-fold, as well as inhibited the formation of (14C)cholesterol from (2-14C)acetate. Reductive methylation of LDL blocked the inhibition of cholesterol synthesis, as well as the stimulation of bile acid synthesis, suggesting that these processes require receptor-mediated uptake. To identify the receptors responsible, competitive binding studies using 125I-labeled apoE-free LDL and 125I-labeled apoE-rich HDL were performed. Both apoE-free LDL and apoE-rich HDL displayed an equal ability to compete for binding of the other, suggesting that a receptor or a group of receptors that recognizes both apolipoproteins is involved. Additional studies show that hepatocytes from cholestyramine-treated rats displayed 2.2- and 3.4-fold increases in the binding of apoE-free LDL and apoE-rich HDL, respectively. These data show for the first time that receptor-mediated uptake of LDL by the liver is intimately linked to processes activating bile acid synthesis.

Junker, L.H.; Davis, R.A. (Univ. of Colorado Health Sciences Center, Denver (USA))



Changes in Non-high-density Lipoprotein Cholesterol Levels and Triglyceride/High-density Lipoprotein Cholesterol Ratios among Patients Randomized to Aripiprazole versus Olanzapine  

PubMed Central

Objective Non-high-density lipoprotein cholesterol (non-HDL-C) and the triglyceride to high-density lipoprotein cholesterol ratio (TG:HDL-C) are predictors of cardiovascular risk. This post-hoc analysis assessed changes in these parameters during treatment with the atypical antipsychotics olanzapine or aripiprazole using pooled data from three randomized, long-term clinical studies in patients with schizophrenia. Methods Data were pooled from one open-label and two double-blind (26- or 52-week) studies in patients randomized to olanzapine (5–20 mg/day) or aripiprazole (15–30 mg/day). Change from baseline in non-HDL-C levels between groups was analyzed in the Observed Case (OC) dataset at each time point and Last Observation Carried Forward (LOCF) dataset at endpoint using analysis of covariance, with treatment as main effect and baseline non-HDL-C as covariate. Differences between groups in median changes from baseline in TG:HDL-C were assessed with Kruskal–Wallis tests. Results This analysis included 546 patients (olanzapine, n=274; aripiprazole, n=272). Mean changes from baseline in non-HDL-C levels were significantly different (p<0.0001) with olanzapine versus aripiprazole at Weeks 26 (+13.0 vs. ?7.5 mg/dL) and 52 (+12.2 vs. ?8.1 mg/dL). Baseline TG:HDL-C was high in the olanzapine (3.73) and aripiprazole (3.79) groups. Differences in median changes from baseline in TG:HDL-C were significant with olanzapine versus aripiprazole at Weeks 26 (+0.22 vs. ?0.54; p<0.0001) and 52 (+0.24 vs. ?0.62; p=0.004). Conclusions Long-term aripiprazole treatment is associated with improvements in lipid profiles of schizophrenia patients versus no improvement or worsening during olanzapine treatment. Consideration of cardiovascular risk is needed when prescribing antipsychotics, as is close monitoring for metabolic changes during treatment. PMID:18973991

Newcomer, John W.; Meyer, Jonathan M.; Baker, Ross A.; Eudicone, James M.; Pikalov, Andrei; Vester-Blokland, Estelle; McQuade, Robert D.; Crandall, David T.; Carson, William H.; Marcus, Ronald N.; L'Italien, Gilbert



Defective endocytosis of low-density lipoprotein in monensin-resistant mutants of the mouse Balb/3T3 cell line.  


Two monensin-resistant clones show similar low-density lipoprotein binding activity but less internalization or degradation of low-density lipoprotein than the parental Balb/3T3 or other resistant clone. Sterol synthesis from radioactive acetate in the resistant mutant, MO-5, is inhibited by more than 70% of control in the presence of tenfold higher amounts of low-density lipoprotein than the dose that inhibits the parental Balb/3T3 to similar level. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity of Balb/3T3 and MO-5 is inhibited by 48% and 27% of control, respectively, in the presence of 10 micrograms/ml of low-density lipoprotein. Colloidal silica gradient centrifugation shows that transport of low-density lipoprotein from the surface membrane to the lysosome is much slower in MO-5 cells than in Balb/3T3 cells. Down regulation of low-density lipoprotein receptors on the cell surface in Balb/3T3 is observed by exposing the cells to 5-15 micrograms/ml low-density lipoprotein, whereas only slight if any down regulation is observed when MO-5 cells are treated with low-density lipoprotein. The altered endocytosis of low-density lipoprotein behaves as a dominant trait in hybrids of MO-5 and THO2-2, a derivative of Balb/3T3 resistant to both ouabain and 6-thioguanine. PMID:3988813

Tomita, K; Ono, M; Masuda, A; Akiyama, S; Kuwano, M



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

SciTech Connect

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

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



Standardization of a Method to Evaluate the Antioxidant Capacity of High-Density Lipoproteins  

PubMed Central

Background: A method to evaluate the antioxidant capacity of high-density lipoprotein (HDL) was developed and standardized. Methods: This method measure conjugated diene (CD) formation and electrophoretic mobility of low-density lipoprotein (LDL) in agarose gels in the presence and absence of HDL. HDL was isolated from 1 mL of plasma within 24 hours and oxidation assays were performed within 6 hours. Oxidation was induced by adding CuSO4. The lag phase increase in CD kinetics and the inhibition of electrophoretic mobility were defined as the HDL antioxidant capacity. Results: The optimal conditions for the CD assay were 2.5 ?M CuSO4, LDL at 0.1 g apoB/L, HDL at 0.1 g apoA-I/L, at 37°C and for 3h 50 min. Agarose electrophoresis at 100 V, at 4°C for 50 min was then performed immediately. CD formation variability was 21.1% for inter-assay CV and 12.7% for intra-assay CV. Electrophoretic mobility was 26.5% for inter-assay CV and 2.4% for intra-assay CV. Correlation analysis showed a significant association between the antioxidant capacity of HDL and its neutral/polar lipid ratio. Conclusions: The method herein described measures of the HDL antioxidant capacity in a reproducible and rapid manner that can be applied to a relatively high number of samples. PMID:23675165

de Juan-Franco, Elena; Perez, Antonio; Ribas, Vicent; Sanchez-Hernandez, Juan Antonio; Blanco-Vaca, Francisco; Ordonez-Llanos, Jordi; Sanchez-Quesada, Jose Luis



Myeloperoxidase: an oxidative pathway for generating dysfunctional high-density lipoprotein.  


Accumulation of low-density lipoprotein (LDL)-derived cholesterol by artery wall macrophages triggers atherosclerosis, the leading cause of cardiovascular disease. Conversely, high-density lipoprotein (HDL) retards atherosclerosis by promoting cholesterol efflux from macrophages by the membrane-associated ATP-binding cassette transporter A1 (ABCA1) pathway. HDL has been proposed to lose its cardioprotective effects in subjects with atherosclerosis, but the underlying mechanisms are poorly understood. One potential pathway involves oxidative damage by myeloperoxidase (MPO), a heme enzyme secreted by human artery wall macrophages. We used mass spectrometry to demonstrate that HDL isolated from patients with established cardiovascular disease contains elevated levels of 3-chlorotyrosine and 3-nitrotyrosine, two characteristic products of MPO. When apolipoprotein A-I (apoA-I), the major HDL protein, was oxidized by MPO, its ability to promote cellular cholesterol efflux by ABCA1 was impaired. Moreover, oxidized apoA-I was unable to activate lecithin:cholesterol acyltransferase (LCAT), which rapidly converts free cholesterol to cholesteryl ester, a critical step in HDL maturation. Biochemical studies implicated tyrosine chlorination and methionine oxygenation in the loss of ABCA1 and LCAT activity by oxidized apoA-I. Oxidation of specific residues in apoA-I inhibited two key steps in cholesterol efflux from macrophages, raising the possibility that MPO initiates a pathway for generating dysfunctional HDL in humans. PMID:20043647

Shao, Baohai; Oda, Michael N; Oram, John F; Heinecke, Jay W



Proteomic Characterization of Human Plasma High Density Lipoprotein Fractionated by Gel Filtration Chromatography  

PubMed Central

Plasma levels of high density lipoprotein cholesterol (HDL-C) are inversely proportional to the incidence of cardiovascular disease. Recent applications of modern proteomic technologies have identified upward of 50 distinct proteins associated with HDL particles with many of these newly discovered proteins implicating HDL in nonlipid transport processes including complement activation, acute phase response and innate immunity. However, almost all MS-based proteomic studies on HDL to date have utilized density gradient ultracentrifugation techniques for HDL isolation prior to analysis. These involve high shear forces and salt concentrations that can disrupt HDL protein interactions and alter particle function. Here, we used high-resolution size exclusion chromatography to fractionate normal human plasma to 17 phospholipid-containing subfractions. Then, using a phospholipid binding resin, we identified proteins that associate with lipoproteins of various sizes by electrospray ionization mass spectrometry. We identified 14 new phospholipid-associated proteins that migrate with traditionally defined HDL, several of which further support roles for HDL in complement regulation and protease inhibition. The increased fractionation inherent to this method allowed us to visualize HDL protein distribution across particle size with unprecedented resolution. The observed heterogeneity across subfractions suggests the presence of HDL particle subpopulations each with distinct protein components that may prove to impart distinct physiological functions. PMID:20718489

Gordon, Scott M.; Deng, Jingyuan; Lu, L. Jason; Davidson, W. Sean



Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations.  

PubMed Central

Interindividual differences in plasma low-density lipoprotein cholesterol (LDL-C) levels reflect both environmental variation and genetic polymorphism, but the specific genes involved and their relative contributions to the variance in LDL-C are not known. In this study we investigated the relationship between plasma LDL-C concentrations and three genes with pivotal roles in LDL metabolism: the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and cholesterol 7alpha-hydroxylase (CYP7). Analysis of 150 nuclear families indicated statistically significant linkage between plasma LDL-C concentrations and CYP7, but not LDLR or APOB. Further sibling pair analyses using individuals with high plasma LDL-C concentrations as probands indicated that the CYP7 locus was linked to high plasma LDL-C, but not to low plasma LDL-C concentrations. This finding was replicated in an independent sample. DNA sequencing revealed two linked polymorphisms in the 5' flanking region of CYP7. The allele defined by these polymorphisms was associated with increased plasma LDL-C concentrations, both in sibling pairs and in unrelated individuals. Taken together, these findings indicate that polymorphism in CYP7 contributes to heritable variation in plasma LDL-C concentrations. Common polymorphisms in LDLR and APOB account for little of the heritable variation in plasma LDL-C concentrations in the general population. PMID:9502769

Wang, J; Freeman, D J; Grundy, S M; Levine, D M; Guerra, R; Cohen, J C



Hepatitis C Virus Stimulates Low-Density Lipoprotein Receptor Expression To Facilitate Viral Propagation  

PubMed Central

ABSTRACT Lipids play a crucial role in multiple aspects of hepatitis C virus (HCV) life cycle. HCV modulates host lipid metabolism to enrich the intracellular milieu with lipids to facilitate its proliferation. However, very little is known about the influence of HCV on lipid uptake from bloodstream. Low-density lipoprotein receptor (LDLR) is involved in uptake of cholesterol rich low-density lipoprotein (LDL) particles from the bloodstream. The association of HCV particles with lipoproteins implicates their role in HCV entry; however, the precise role of LDLR in HCV entry still remains controversial. Here, we investigate the effect of HCV infection on LDLR expression and the underlying mechanism(s) involved. We demonstrate that HCV stimulates LDLR expression in both HCV-infected Huh7 cells and in liver tissue from chronic hepatitis C patients. Fluorescence activated cell sorting and immunofluorescence analysis revealed enhanced cell surface and total expression of LDLR in HCV-infected cells. Increased LDLR expression resulted in the enhanced uptake of lipoprotein particles by HCV-infected cells. Analysis of LDLR gene promoter identified a pivotal role of sterol-regulatory element binding proteins (SREBPs), in the HCV-mediated stimulation of LDLR transcription. In addition, HCV negatively modulated the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that facilitates LDLR degradation. Ectopic expression of wild-type PCSK9 or gain-of-function PCSK9 mutant negatively affected HCV replication. Overall, our results demonstrate that HCV regulates LDLR expression at transcriptional and posttranslational level via SREBPs and PCSK9 to promote lipid uptake and facilitate viral proliferation. IMPORTANCE HCV modulates host lipid metabolism to promote enrichment of lipids in intracellular environment, which are essential in multiple aspects of HCV life cycle. However, very little is known about the influence of HCV on lipid uptake from the bloodstream. LDLR is involved in uptake of cholesterol rich lipid particles from bloodstream. In this study, we investigated the effect of HCV on LDLR expression and the underlying mechanism triggered by the virus to modulate LDLR expression. Our observations suggest that HCV upregulates LDLR expression at both the protein and the transcript levels and that this upregulation likely contributes toward the uptake of serum lipids by infected hepatocytes. Abrogation of HCV-mediated upregulation of LDLR inhibits serum lipid uptake and thereby perturbs HCV replication. Overall, our findings highlight the importance of serum lipid uptake by infected hepatocytes in HCV life cycle. PMID:24352472

Syed, Gulam Hussain; Tang, Huihui; Khan, Mohsin; Hassanein, Tarek; Liu, Jingwen



Passage of Low-density Lipoproteins Through Bruch's Membrane and Choroid  

PubMed Central

Plasma lipoproteins are thought to transport cholesterol, vitamins and carotenoids to the retinal pigment epithelium (RPE) for ultimate use by the photoreceptors. However, to reach the RPE, these lipoprotein particles must cross Bruch’s membrane. We examined the reflection coefficient of Bruch’s membrane (BrM) to low-density lipoprotein (LDL). Bruch’s membrane and choroid were removed from 47 bovine eyes. Specimens were placed in a Ussing chamber and perfused with phosphate-buffered saline (PBS) with (31 specimens) or without (16 specimens) fluorescent low-density lipoproteins (DiI-LDL). The hydraulic conductivity of the tissue was determined for both calf and cow eyes. In the perfusions with DiI-LDL, the fluorescence intensity emitted by DiI-LDL in the efflux was measured and the reflection coefficient of BrM/choroid preparations to DiI-LDL determined. Leakage tests were done to confirm tissue integrity. Several specimens were examined using scanning electron microscopy (SEM) to examine tissue integrity before and after perfusion. Leak testing confirmed that BrM was intact both before and after perfusion. The average hydraulic conductivity of BrM/choroid perfusion of calf eyes with PBS alone was 1.42 ± 0.55 ×10?9 m/s/Pa (mean ± SD, n = 11). The average hydraulic conductivity of the cow eyes was 4.94 ± 1.48 ×10?10 m/s/Pa (n = 5), nearly a 3-fold decrease with age. While the flow rate remained constant during the PBS perfusions, it decreased as a function of time during perfusion with DiI-LDLs. Our major finding was of fluorescence in the effluent collected in all perfusions with DiI-LDLs, demonstrating passage of LDL through the tissue. The average reflection coefficient of calf BrM/choroid preparations to DiI-LDL was 0.58 ± 0.25 (n = 23); a similar distribution of reflection coefficients was seen in tissue from cow eyes (0.51 ± 0.33, n = 8). Our data suggested that the DiI-LDL was modestly hindered and/or captured by the tissue. This might explain the progressive decrease of hydraulic conductivity with continued perfusion of DiI-LDL. PMID:22063729

Cankova, Zdravka; Huang, Jiahn-Dar; Kruth, Howard S.; Johnson, Mark



N-Succinyl-chitosan nanoparticles coupled with low-density lipoprotein for targeted osthole-loaded delivery to low-density lipoprotein receptor-rich tumors  

PubMed Central

N-Succinyl-chitosan (NSC) was synthesized and NSC nanoparticles (NPs) with loaded osthole (Ost) (Ost/NSC-NPs) were prepared by emulsion solvent diffusion. Subsequently, low-density lipoprotein (LDL)-mediated NSC-NPs with loaded Ost (Ost/LDL-NSC-NPs) were obtained by coupling LDL with Ost/NSC-NPs through amide linkage. The average particle size of Ost/NSC-NPs was approximately 145 nm, the entrapment efficiency was 78.28%±2.06%, and the drug-loading amount was 18.09%±0.17%. The release of Ost from Ost/NSC-NPs in vitro showed a more evident sustained effect than the native material. The half maximal inhibitory concentration of Ost/LDL-NSC-NPs was only 16.23% that of the free Ost at 24 hours in HepG2 cells. Ost inhibited HepG2 cell proliferation by arresting cells in the synthesis phase of the cell cycle and by triggering apoptosis. Cellular uptake and subcellular localization in vitro and near-infrared fluorescence real-time imaging in vivo showed that Ost/LDL-NSC-NPs had high targeting efficacy. Therefore, LDL-NSC-NPs are a promising system for targeted Ost delivery to liver tumor. PMID:24966673

Zhang, Chun-ge; Zhu, Qiao-ling; Zhou, Yi; Liu, Yang; Chen, Wei-liang; Yuan, Zhi-Qiang; Yang, Shu-di; Zhou, Xiao-feng; Zhu, Ai-jun; Zhang, Xue-nong; Jin, Yong



Effect of Fluid Shear Stress on Endocytosis of Heparan Sulfate and Low-density Lipoproteins  

PubMed Central

Hemodynamic stress is a critical factor in the onset of atherosclerosis such that reduced rates of shear stress occurring at regions of high curvature are more prone to disease. The level of shear stress has direct influence on the thickness and integrity of the glycocalyx layer. Here we show that heparan sulfate, the main component of the glycocalyx layer, forms an intact layer only on cell surfaces subjected to shear, and not under static conditions. Furthermore, receptor-mediated endocytosis of heparan sulfate and low-density liporoteins is not detectable in cells exposed to shear stress. The internalized heparan sulfate and low-density lipoproteins are colocalized as shown by confocal imaging. PMID:18309375

Barkefors, Irmeli; Aidun, Cyrus K.; Ulrika Egertsdotter, E. M.



Streptococcal Serum Opacity Factor Increases Hepatocyte Uptake of Human Plasma High Density Lipoprotein-Cholesterol1  

PubMed Central

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 ~400,000 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. [3H]CE uptake by HepG2 and Huh7 cells from HDL after SOF treatment, which transfers >90% of HDL-CE to CERM, was respectively 2.4 and 4.5 times faster than from control HDL. CERM-[3H]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-[3H]CE uptake by both receptors. RAP and heparin inhibit CERM-[3H]CE but not HDL-[3H]CE uptake thereby implicating LRP-1 and cell surface proteoglycans in this process. These data demonstrate that SOF treatment of HDL increases CE uptake via multiple hepatic apo E receptors. In so doing, SOF might increase hepatic disposal of plasma cholesterol in a way that is therapeutically useful. PMID:20879789

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



Starvation of low-density lipoprotein-derived cholesterol induces bradyzoite conversion in Toxoplasma gondii  

PubMed Central

Background Lacking enzymes for sterol synthesis, the intracellular protozoan Toxoplasma gondii scavenges cholesterol from host cells to multiply. T. gondii has a complex life cycle consisting of two asexual stages; the proliferative stage (tachyzoite), and the latent stage characterized by tissue cysts (bradyzoite). In vitro, bradyzoite development can be induced by mimicking host immune response stressors through treatment with IFN-?, heat shock, nitric oxide, and high pH. However, the extent to which host nutrients contribute to stage conversion in T. gondii is unknown. In this study, we examined the impact of host cholesterol levels on stage conversion in this parasite. Methods Growth of T. gondii tachyzoites (ME49 strain) was investigated in Chinese hamster ovary (CHO) cells using various concentrations of low-density lipoprotein (LDL), oleic acid, or glucose. Squalestatin, which is an inhibitor of squalene synthase and is, therefore, an inhibitor of sterol synthesis, was used to treat the CHO cells. Tachyzoite to bradyzoite conversion rates were analyzed by indirect fluorescent antibody tests. Results Parasite growth was significantly enhanced by addition of exogenous LDL, whereas no such enhancement occurred with oleic acids or glucose. In ME49, growth inhibition from squalestatin treatment was not obvious. Although growth of the RH strain was unaffected by squalestatin in the presence of lipoprotein, in its absence growth of this strain was suppressed. The frequency of BAG1-positive vacuoles in ME49 increased under lipoprotein-free conditions. However, addition of exogenous LDL did not increase tachyzoite to bradyzoite conversion in this strain. Furthermore, treatment with squalestatin did not enhance stage conversion. Conclusion Our results suggest that LDL-derived cholesterol levels play a crucial role in bradyzoite conversion in T. gondii. PMID:24885547



Role of high density lipoproteins in the biodistribution of two radioiodinated probes in the rat  

SciTech Connect

Two radioiodinated probes, /sup 125/I-cholesteryl oleate (/sup 125/I-CO), a derivative of a natural constituent of lipoproteins, and 1-(2-chlorophenyl)-1-(4(/sup 125/I)iodophenyl)-2,2-dichlorethane (/sup 125/I-DDD), an analog of the adrenolytic drug o,p'-DDD (mitotane), were selected to study the role of lipoproteins in drug disposition and to examine the ability of these vehicles to direct foreign molecules to specific tissues. In vivo and in vitro techniques were utilized to associate these probes with rat high density lipoproteins (HDL). Tissue distribution studies indicated that prior incorporation of /sup 125/I-CO into rat HDL increased the uptake of /sup 125/I-CO by rat adrenal, which was dramatically enhanced when this preparation was administered to animals made hypolipidemic with 4-aminopyrazolo(3,4-d)-pyrimidine (4-APP). Acetylation of HDL labeled with /sup 125/I-CO provided evidence that the observed uptake into the adrenal was via a receptor-mediated process. In contrast with these results, prior association of /sup 125/I-DDD with rat HDL failed to alter the ability of this compound to accumulate in adrenal tissue of normal or hypolipidemic animals. Polyacrylamide gel electrophoresis (PAGE) was utilized to examine the stability of the association of /sup 125/I-CO and /sup 125/I-DDD with rat HDL. These results suggested that /sup 125/I-CO was associated with the lipophilic core of HDL, whereas /sup 125/I-DDD appeared to be partially associated with the surface components of HDL. Saturation of surface components with stable o,p'-DDD offered data to suggest that this binding to apoproteins may disrupt the normal receptor-mediated uptake process.

Pohland, R.C.; Counsell, R.E.



Reversal of hyperlipidaemia in apolipoprotein C1 transgenic mice by adenovirus-mediated gene delivery of the low-density-lipoprotein receptor, but not by the very-low-density-lipoprotein receptor.  

PubMed Central

We have shown previously that human apolipoprotein (apo)C1 transgenic mice exhibit hyperlipidaemia, due primarily to an impaired clearance of very-low-density lipoprotein (VLDL) particles from the circulation. In the absence of at least the low-density-lipoprotein receptor (LDLR), it was shown that APOC1 overexpression in transgenic mice inhibited the hepatic uptake of VLDL via the LDLR-related protein. In the present study, we have now examined the effect of apoC1 on the binding of lipoproteins to both the VLDL receptor (VLDLR) and the LDLR. The binding specificity of the VLDLR and LDLR for apoC1-enriched lipoprotein particles was examined in vivo through adenovirus-mediated gene transfer of the VLDLR and the LDLR [giving rise to adenovirus-containing (Ad)-VLDLR and Ad-LDLR respectively] in APOC1 transgenic mice, LDLR-deficient (LDLR-/-) mice and wild-type mice. Remarkably, Ad-VLDLR treatment did not reduce hyperlipidaemia in transgenic mice overexpressing human APOC1, irrespective of both the level of transgenic expression and the presence of the LDLR, whereas Ad-VLDLR treatment did reverse hyperlipidaemia in LDLR-/- and wild-type mice. On the other hand, Ad-LDLR treatment strongly decreased plasma lipid levels in these APOC1 transgenic mice. These results suggest that apoC1 inhibits the clearance of lipoprotein particles via the VLDLR, but not via the LDLR. This hypothesis is corroborated by in vitro binding studies. Chinese hamster ovary (CHO) cells expressing the VLDLR (CHO-VLDLR) or LDLR (CHO-LDLR) bound less APOC1 transgenic VLDL than wild-type VLDL. Intriguingly, however, enrichment with apoE enhanced dose-dependently the binding of wild-type VLDL to CHO-VLDLR cells (up to 5-fold), whereas apoE did not enhance the binding of APOC1 transgenic VLDL to these cells. In contrast, for binding to CHO-LDLR cells, both wild-type and APOC1 transgenic VLDL were stimulated upon enrichment with apoE. From these studies, we conclude that apoC1 specifically inhibits the apoE-mediated binding of triacylglycerol-rich lipoprotein particles to the VLDLR, whereas apoC1-enriched lipoproteins can still bind to the LDLR. The variability in specificity of these lipoprotein receptors for apoC1-containing lipoprotein particles provides further evidence for a regulatory role of apoC1 in the delivery of lipoprotein constituents to different tissues on which these receptors are located. PMID:10024503

Jong, M C; van Dijk, K W; Dahlmans, V E; Van der Boom, H; Kobayashi, K; Oka, K; Siest, G; Chan, L; Hofker, M H; Havekes, L M



Increased low density lipoprotein degradation in aorta of irradiated mice is inhibited by preenrichment of low density lipoprotein with a -tocopherol  

Microsoft Academic Search

We previously reported that upper thoracic expo- sure to ionizing radiation (IR) accelerates fatty streak forma- tion in C57BL\\/6 mice and that such effects are inhibited by overexpression of the antioxidant enzyme CuZn-superoxide dismutase (SOD). Notably, IR-accelerated lesion formation is strictly dependent on a high fat diet (i.e., atherogenic lipoproteins) but does not involve alterations in circulating lipid or lipoprotein

D. L. Tribble; R. M. Krauss; B. M. Chu; E. L. Gong; B. R. Kullgren; J. O. Nagy; M. La Belle


Endocytosis of a cytotoxic human high density lipoprotein results in disruption of acidic intracellular vesicles and subsequent killing of African trypanosomes  

PubMed Central

The host range of Trypanosoma brucei brucei is restricted by the cytolytic effects of human serum high-density lipoprotein (HDL). The lytic activity is caused by a minor subclass of human serum HDL called trypanosome lytic factor (TLF). TLF binds in the flagellar pocket to specific TLF-binding sites. Internalization and localization of TLF to a population of endocytic vesicles, and ultimately large lysosome-like vesicles, precedes lysis of T. b. brucei. The membranes of these large vesicles are disrupted by the accumulation of TLF particles. Inhibitor studies with lysosomotropic amines have shown these large vesicles to be acidic in nature and that prevention of their rupture spares the cells from TLF-mediated lysis. Furthermore, leupeptin inhibition suggests that a thioprotease may be involved in the mechanism of TLF- mediated lysis of T. b. brucei. Based on these results, we propose a lytic mechanism involving cell surface binding, endocytosis and lysosomal targeting. This is followed by lysosomal disruption and subsequent autodigestion of the cell. PMID:8027174



Endocytosis of a cytotoxic human high density lipoprotein results in disruption of acidic intracellular vesicles and subsequent killing of African trypanosomes.  


The host range of Trypanosoma brucei brucei is restricted by the cytolytic effects of human serum high-density lipoprotein (HDL). The lytic activity is caused by a minor subclass of human serum HDL called trypanosome lytic factor (TLF). TLF binds in the flagellar pocket to specific TLF-binding sites. Internalization and localization of TLF to a population of endocytic vesicles, and ultimately large lysosome-like vesicles, precedes lysis of T. b. brucei. The membranes of these large vesicles are disrupted by the accumulation of TLF particles. Inhibitor studies with lysosomotropic amines have shown these large vesicles to be acidic in nature and that prevention of their rupture spares the cells from TLF-mediated lysis. Furthermore, leupeptin inhibition suggests that a thioprotease may be involved in the mechanism of TLF-mediated lysis of T. b. brucei. Based on these results, we propose a lytic mechanism involving cell surface binding, endocytosis and lysosomal targeting. This is followed by lysosomal disruption and subsequent autodigestion of the cell. PMID:8027174

Hager, K M; Pierce, M A; Moore, D R; Tytler, E M; Esko, J D; Hajduk, S L



Low- and high-density lipoproteins as mitogenic factors for vascular smooth muscle cells: individual, additive and synergistic effects.  


The mitogenic activities of low (LDL)- and high (HDL)-density lipoproteins have been examined in cultures of human vascular smooth muscle cells (VSMC). LDL and HDL3 dose-dependently (EC50 values approximately 50 micrograms/ml) stimulated DNA and protein synthesis ([3H]-thymidine and [3H]-leucine incorporation, respectively) in the absence of exogenously added mitogens. The synthetic responses of VSMC to combinations of LDL and HDL3 were additive, indicating that each lipoprotein mediates discrete effects. LDL or HDL3 promoted VSMC proliferation under strict mitogen-free conditions, but this growth response was not sustained. VSMC exposed to combinations of lipoproteins (either LDL or HDL3) and growth factors (either PDGF-BB, EGF, bFGF or IGF) exhibited synergistic DNA synthesis responses. In the combined presence of PDGF-BB and either LDL or HDL3, VSMC proliferation was sustained. Anionized lipoprotein preparations (oxidized, acetylated, carbamylated or malonimylated) also stimulated DNA and protein synthesis. Since the antioxidant beta-hydroxylated toluene did not block the effect of native LDL on DNA synthesis, and fucoidin, a specific competitor for the 'scavenger' receptor, did not inhibit oxidized LDL-induced DNA synthesis, activation of mitogenic signals by lipoproteins does not depend on lipid peroxidation. Rather, the apparent intrinsic mitogenic potential of lipoproteins may depend upon their direct activation of replication-coupled signal transduction systems. PMID:7578801

Resink, T J; Bochkov, V N; Hahn, A W; Philippova, M P; Bühler, F R; Tkachuk, V A



The Complex Fate in Plasma of Gadolinium Incorporated into High-Density Lipoproteins Used for Magnetic Imaging of Atherosclerotic Plaques  

PubMed Central

We have previously reported enhancing the imaging of atherosclerotic plaques in mice using reconstituted high density lipoproteins (HDL) as nanocarriers for the MRI contrast agent gadolinium (Gd). This study focuses on the underlying mechanisms of Gd delivery to atherosclerotic plaques. HDL, LDL, and VLDL particles containing Gd chelated to phosphatidyl ethanolamine (DTPA-DMPE) and a lipidic fluorophore were used to demonstrate the transfer of Gd-phospholipids among plasma lipoproteins in vitro and in vivo. To determine the basis of this transfer, the roles of phospholipid transfer protein (PLTP) and lipoprotein lipase (LpL) in mediating the migration of Gd-DTPA-DMPE among lipoproteins were investigated. The results indicated that neither was an important factor, suggesting that spontaneous transfer of Gd-DTPA-DMPE was the most probable mechanism. Finally, two independent mouse models were used to quantify the relative contributions of HDL and LDL reconstituted with Gd-DTPA-DMPE to plaque imaging enhancement by MR. Both sets of results suggested that Gd-DTPA-DMPE originally associated with LDL was about twice as effective as that injected in the form of Gd-HDL, and that some of Gd-HDL’s effectiveness in vivo is indirect through transfer of the imaging agent to LDL. In conclusion, the fate of Gd-DTPA-DMPE associated with a particular type of lipoprotein is complex, and includes its transfer to other lipoprotein species that are then cleared from the plasma into tissues. PMID:23617731

Barazza, Alessandra; Blachford, Courtney; Even-Or, Orli; Joaquin, Victor A.; Briley-Saebo, Karen C.; Chen, Wei; Jiang, Xian-Cheng; Mulder, Willem J. M.; Cormode, David P.; Fayad, Zahi A.; Fisher, Edward A.



Dietary alpha-cyclodextrin lowers low-density lipoprotein cholesterol and alters plasma fatty acid profile in low-density lipoprotein receptor knockout mice on a high-fat diet.  


High dietary intake of saturated fat and cholesterol, and elevated low-density lipoprotein cholesterol levels are some of the modifiable risk factors for cardiovascular disease. Alpha-cyclodextrin (a-CD) when given orally has been shown in rats to increase fecal saturated fat excretion and to reduce blood total cholesterol levels in obese hypertriglyceridemic subjects with type 2 diabetes mellitus. In this study, the effects of dietary a-CD on lipid metabolism in low-density lipoprotein receptor knockout mice were investigated. Low-density lipoprotein receptor knockout mice were fed a "Western diet" (21% milk fat) with or without 2.1% of a-CD (10% of dietary fat content) for 14 weeks. At sacrifice, there was no difference in body weight; but significant decreases were observed in plasma cholesterol (15.3%), free cholesterol (20%), cholesterol esters (14%), and phospholipid (17.5%) levels in mice treated with alpha-CD compared with control mice. The decrease in total cholesterol was primarily in the proatherogenic apolipoprotein B-containing lipoprotein fractions, with no significant change in the high-density lipoprotein fraction. Furthermore, alpha-CD improved the blood fatty acid profile, reducing the saturated fatty acids (4.5%) and trans-isomers (11%) while increasing (2.5%) unsaturated fatty acids. In summary, the addition of alpha-CD improved the lipid profile by lowering proatherogenic lipoproteins and trans-fatty acids and by decreasing the ratio of saturated and trans-fatty acids to polyunsaturated fatty acids (-5.8%), thus suggesting that it may be useful as a dietary supplement for reducing cardiovascular disease. PMID:18640380

Wagner, Elke Maria; Jen, Kai-Lin Catherine; Artiss, Joseph Donald; Remaley, Alan Thomas




PubMed Central

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

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



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

PubMed Central

Introduction. Cardioprotective effect of high density lipoprotein (HDL) is, in part, dependent on its related enzyme, paraoxonase 1 (PON1). Fatty acid composition of HDL could affect its size and structure. On the other hand, PON1 activity is directly related to the structure of HDL. This study was designed to investigate the association between serum PON1 activity and fatty acid composition of HDL in healthy men. Methods. One hundred and forty healthy men participated in this research. HDL was separated by sequential ultracentrifugation, and its fatty acid composition was analyzed by gas chromatography. PON1 activity was measured spectrophotometrically using paraxon as substrate. Results. Serum PON1 activity was directly correlated with the amount of stearic acid and dihomo-gamma-linolenic acid (DGLA). PON1/HDL-C was directly correlated with the amount of miristic acid, stearic acid, and DGLA and was inversely correlated with total amount of ?6 fatty acids of HDL. Conclusion. The fatty acid composition of HDL could affect the activity of its associated enzyme, PON1. As dietary fats are the major determinants of serum lipids and lipoprotein composition, consuming some special dietary fatty acids may improve the activity of PON1 and thereby have beneficial effects on health. PMID:24167374

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



Effect of chronic renal failure on high-density lipoprotein kinetics  

SciTech Connect

Plasma lipid and lipoprotein concentration and high density lipoprotein (HDL) kinetics were determined in control subjects and patients with chronic renal failure (CRF). Results demonstrated that plasma triglyceride (TG) concentration was significantly higher (P less than 0.001) in patients with CRF, associated with a significant increase in plasma VLDL-cholesterol (P less than 0.002) and a significant decrease (P less than 0.05) in plasma HDL-cholesterol concentration. The rate of removal of {sup 125}I-apoAI/HDL from plasma was slower (P less than 0.001) in the patients with CRF, resulting in an increase in the residence time of {sup 125}I-apoAI/HDL (P less than 0.001) and a decrease in the fractional catabolic rate (P less than 0.001). Since plasma apoAI concentration was lower in patients with CRF, total apoAI/HDL synthetic rate was also significantly (P less than 0.05) decreased. These data provide support for the view that low plasma HDL-cholesterol concentrations in patients with CRF are related to decreases in the synthetic rate of apoAI/HDL.

Fuh, M.M.; Lee, C.M.; Jeng, C.Y.; Shen, D.C.; Shieh, S.M.; Reaven, G.M.; Chen, Y.D. (Stanford Univ. School of Medicine, CA (USA))



High relaxivity gadolinium modified high density lipoproteins as MRI contrast agents  

PubMed Central

There is an ongoing desire to produce high relaxivity, Gd-based MRI contrast agents. These may allow for lower doses to be used, which is especially important in view of the current safety concerns surrounding Gd in patients. Here we report the synthesis of a high relaxivity MRI contrast agent, by incorporating Gd-chelating lipids that coordinate two water molecules into high density lipoprotein (q=2 HDL). We compared the properties of q=2 HDL with those of an analogous HDL particle labeled with Gd-chelating lipids that coordinate only one water molecule (q=1 HDL). We found that the q=2 HDL possessed an elevated r1 of 41 mM?1s?1 compared to 9 mM?1s?1 for q=1 HDL at 20 MHz, but the q=2 HDL exhibited high R2* values at high fields, precluding imaging above 128 MHz. While carrying out this investigation we observed that enlarged, disrupted particles were formed when the synthesis was carried out above the lipid critical micelle concentration (CMC), indicating the importance of synthesis below the CMC when modifying lipoproteins in this manner. The high relaxivity of q=2 HDL means it will be an efficacious contrast agent for future MR imaging studies. PMID:19361222

Briley-Saebo, Karen C.; Geninatti-Crich, Simonetta; Cormode, David P.; Barazza, Alessandra; Mulder, Willem J. M.; Chen, Wei; Giovenzana, Giovanni B.; Fisher, Edward A.; Aime, Silvio; Fayad, Zahi A.



Onset of lipoprotein-supported steroidogenesis in differentiating granulosa cells of rats: cellular events involved in mediating FSH-enhanced uptake of low-density lipoproteins  

SciTech Connect

Luteal cells use lipoproteins as the main source of cholesterol in steroidogenesis. However, little is known about the mechanisms underlying hormonal control of lipoprotein uptake. Thus, the authors tested the hypothesis that FSH and androgens regulate low density lipoprotein (LDL)-supported steroidogenesis in maturing granulosa cells by affecting receptor-mediated endocytosis of LDL at a cellular level. For this, immature ovarian granulosa cells were cultured with or without hormones, compactin (de novo synthesis inhibitor), or unlabeled or labeled (/sup 125/I or gold particles) LDL. Nonhormone-treated cultures produced little progestin; FSH and FSH/androstenedione stimulated steroid secretion. Progestin production by hormone-, but not nonhormone-, treated cultures was decreased by compactin, suggesting that de novo synthesis provided sterol for steroidogenesis. EM quantitation of cells exposed to gold-LDL at 37/sup 0/C revealed that, compared to nonhormone-treated cells, FSH-treated cells (1) bound and internalized more gold-LDL, (2) had a smaller percentage of gold-LDL at their surfaces, (3) displayed a faster apparent rate of LDL internalization and delivery to lysosomes, and (4) contained more gold-labeled lysosomes. Data from biochemical studies in which /sup 125/I-LDL was used supported the morphological findings. In conclusion, this study demonstrates that FSH has important effects at the cellular level on LDL uptake, which seem to underlie the striking increase in progestin production accompanying granulosa cell differentiation.

Foster, J.D.



Potential role of the interaction between equine estrogens, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in the prevention of coronary heart and neurodegenerative diseases in postmenopausal women  

Microsoft Academic Search

BACKGROUND: An inverse relationship between the level of high-density lipoprotein (HDL) and coronary heart disease (CHD) has been reported. In contrast, oxidized HDL (oHDL) has been shown to induce neuronal death and may play an important role in the pathogenesis of CHD. In the present study we have investigated a: the effect of various equine estrogens on HDL oxidation, b:

Joel Perrella; Mauricio Berco; Anthony Cecutti; Alan Gerulath; Bhagu R Bhavnani



Beta-very low density lipoprotein is sequestered in surface-connected tubules in mouse peritoneal macrophages  

PubMed Central

beta-very low density lipoprotein (VLDL) is a large lipoprotein with multiple apoprotein E (apoE) molecules that bind to the LDL receptors on mouse macrophages. Even though they bind to the same receptor, the endocytic processing of beta-VLDL differs from low density lipoprotein (LDL). LDL is rapidly delivered to perinuclear lysosomes and degraded, but much of the beta-VLDL is retained in peripheral compartments for several minutes. We have investigated the properties of these peripheral compartments. Measurement of the pH was made using FITC- phosphatidylethanolamine incorporated into the beta-VLDL, and we found that the peripheral compartments were near neutral in pH. These peripheral, beta-VLDL containing compartments were poorly accessible to antibodies, but a low molecular weight fluorescence quencher (trypan blue) entered the compartments within a few seconds. Intermediate voltage EM of cells labeled with colloidal-gold-beta-VLDL revealed that the peripheral compartments are tubular, surface-connected invaginations. Kinetic studies with fluorescent beta-VLDL showed that the compartments become fully sealed with a half-time of 6 min, and the beta-VLDL is then delivered rapidly to perinuclear lysosomes. By monitoring fluorescence energy transfer between lipid analogs incorporated into the beta-VLDL, some processing of the lipoprotein in the peripheral tubular compartments is demonstrated. The novel mode of uptake of beta-VLDL may account for the high cholesterol ester accumulation induced by this lipoprotein. PMID:8253839



High-density lipoproteins in the prevention of cardiovascular disease: changing the paradigm.  


High-density-lipoprotein cholesterol (HDL-C) has been identified in population studies as an independent inverse predictor of cardiovascular events. Although the causal nature of this association has been questioned, HDL and its major protein, apolipoprotein (apo)A1, have been shown to prevent and reverse atherosclerosis in animal models. In addition, HDL and apoA1 have several putatively atheroprotective functions, such as the ability to promote efflux of cholesterol from macrophages in the artery wall, inhibit vascular inflammation, and enhance endothelial function. Therefore, HDL-C and apoA1 have been investigated as therapeutic targets for coronary heart disease. However, recent clinical trials with drugs that raise HDL-C, such as niacin and inhibitors of cholesteryl ester transfer protein, have been disappointing. Here, we review the current state of the science regarding HDL as a therapeutic target. PMID:24713591

Tuteja, S; Rader, D J



Malonyldialdehyde and glyoxal act differently on low-density lipoproteins and endotheliocytes.  


Under some pathological conditions, the natural dicarbonyl compounds can accumulate in the blood. The examples are malonyldialdehyde (MDA) formed as a secondary product of lipid peroxidation of unsaturated fatty acids during atherosclerosis, and glyoxal (GOX), a homolog of MDA, which accumulates during glucose autoxidation in patients with diabetes mellitus. This study compared the influence of both dicarbonyl compounds on low-density lipoproteins (LDL) and the membrane of endotheliocytes. In comparison with GOX, MDA induced more pronounced changes in physical and chemical properties of LDL particles. On the other hand, GOX-modified LDL particles were more prone to oxidation and aggregation than MDA-modified LDL. Incubation of endotheliocytes with MDA increased cell mechanical stiffness in contrast to incubation with GOX, which decreased it. PMID:25064448

Kumskova, Elena M; Antonova, Olga A; Balashov, Sergey A; Tikhaze, Alla K; Melkumyants, Arthur M; Lankin, Vadim Z



Evaluation of various electrode materials for detection of oxidized low-density lipoproteins.  


Measurement of oxidized low-density lipoprotein (LDL) generated by oxidative stress of various kinds might be useful for evaluating the risk of cardiovascular disease. We evaluated some electrode materials to detect oxidized LDL electrochemically. Some carbon nanotube dispersions were studied as electrode materials. Native LDL was isolated from normal human serum using ultracentrifugation. Oxidized LDL was prepared by treating the native LDL with CuSO4. Electrodes were fabricated by depositing the nanotube dispersion on a gold electrode, with subsequent drying. The potential change of the electrode against a reference electrode was monitored before and after adding native LDL or oxidized LDL. Only acid-treated carbon nanotubes were able to discriminate both LDL preparations, perhaps because of the carboxylic acid groups introduced on the nanotube by acid treatment. PMID:23627060

Takeda, Seiji; Hui, Shu-Ping; Fuda, Hirotoshi; Jin, Shigeki; Sakurai, Toshihiro; Ishii, Atsushi; Mukasa, Koichi; Sueoka, Kazuhisa; Chiba, Hitoshi



Treating low high-density lipoprotein cholesterol: what is the evidence?  

PubMed Central

Epidemiological studies have shown an inverse association between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD) risk. However, genetic and interventional studies have failed to consistently support this relationship. There is an increasing body of evidence that the function of HDL, including its antiatherogenic properties and its reverse cholesterol transport activity, has a greater impact on CVD risk compared with levels of HDL alone. Targeting HDL has become a growing interest. Nevertheless, raising HDL pharmacologically has failed to show a considerable, if any, impact on cardiovascular outcome. Efforts should focus on improving HDL quality in addition to raising HDL levels when developing new therapies. Ongoing and future research will help determine the most safe and effective approach to improve cardiovascular outcome and establish the safety, efficacy and impact on atherosclerosis of the emerging HDL-raising therapies. PMID:24696776

Hage, Mirella P.



New insights into the mechanism of low high-density lipoprotein cholesterol in obesity  

PubMed Central

Obesity, a significant risk factor for various chronic diseases, is universally related to dyslipidemia mainly represented by decreasing high-density lipoprotein cholesterol (HDL-C), which plays an indispensible role in development of cardiovascular disease (CVD). However, the mechanisms underlying obesity and low HDL-C have not been fully elucidated. Previous studies have focused on the alteration of HDL catabolism in circulation following elevated triglyceride (TG). But recent findings suggested that liver and fat tissue played pivotal role in obesity related low HDL-C. Some new molecular pathways like microRNA have also been proposed in the regulation of HDL metabolism in obesity. This article will review recent advances in understanding of the potential mechanism of low HDL-C in obesity. PMID:21988829



Apolipoprotein B100 quality control and the regulation of hepatic very low density lipoprotein secretion.  


Apolipoprotein B (apoB) is the main protein component of very low density lipoprotein (VLDL) and is necessary for the assembly and secretion of these triglyceride (TG)-rich particles. Following release from the liver, VLDL is converted to low density lipoprotein (LDL) in the plasma and increased production of VLDL can therefore play a detrimental role in cardiovascular disease. Increasing evidence has helped to establish VLDL assembly as a target for the treatment of dyslipidemias. Multiple factors are involved in the folding of the apoB protein and the formation of a secretion-competent VLDL particle. Failed VLDL assembly can initiate quality control mechanisms in the hepatocyte that target apoB for degradation. ApoB is a substrate for endoplasmic reticulum associated degradation (ERAD) by the ubiquitin proteasome system and for autophagy. Efficient targeting and disposal of apoB is a regulated process that modulates VLDL secretion and partitioning of TG. Emerging evidence suggests that significant overlap exists between these degradative pathways. For example, the insulin-mediated targeting of apoB to autophagy and postprandial activation of the unfolded protein response (UPR) may employ the same cellular machinery and regulatory cues. Changes in the quality control mechanisms for apoB impact hepatic physiology and pathology states, including insulin resistance and fatty liver. Insulin signaling, lipid metabolism and the hepatic UPR may impact VLDL production, particularly during the postprandial state. In this review we summarize our current understanding of VLDL assembly, apoB degradation, quality control mechanisms and the role of these processes in liver physiology and in pathologic states. PMID:25013401

Fisher, Eric; Lake, Elizabeth; McLeod, Roger S



Metabolism of triglyceride-rich nascent rat hepatic high density lipoproteins  

SciTech Connect

Nascent high density lipoprotein (HDL) and nascent very low density lipoprotein (VLDL) were isolated from rat livers that had been perfused with (3H)glycerol to label the triglyceride. When injected into intact rats, the labeled HDL-triglyceride disappeared as rapidly as the VLDL-triglyceride, with only 10% of the injected label remaining in the plasma after 30 min. The protein moiety of nascent HDL was labeled with (35S)methionine in a similar fashion and the labeled nascent HDL was separated into nonretained (NR) and retained (R) fractions by heparin-Sepharose affinity chromatography. When injected into rats, 55% of the injected label in nascent fraction NR and 72% of that in nascent fraction R was recovered from plasma at 30 min, compared to only 10% of the triglyceride label from unfractionated nascent HDL, indicating dissociation of triglyceride and apolipoprotein clearance. The plasma decay curves for both triglyceride and protein were biexponential. By 5 min, 15% of the 35S label remaining in plasma represented apoE and apoC that had been transferred from nascent HDL fractions NR and R to the d less than 1.063 g/ml fraction of plasma. Plasma HDL was labeled in vivo with (35S)methionine, separated into fractions NR and R, and the clearance of the two plasma HDL fractions was compared with that of the corresponding nascent HDL fractions. Except for a faster rate of removal of the nascent HDL fractions during the first 5 min, the serum decay curves were very similar.

Winkler, K.E.; Marsh, J.B. (Medical College of Pennsylvania, Philadelphia (USA))



High-density lipoproteins in sepsis and septic shock: metabolism, actions, and therapeutic applications.  


Sepsis and septic shock are important causes of morbidity and lethality in noncoronary intensive care units. Circulating levels of high-density lipoproteins (HDLs) are reduced in sepsis/septic shock, and the magnitude of this reduction is positively correlated with the severity of the illness. The mechanisms underlying this phenomenon are incompletely understood, although increased levels of several acute-phase proteins, including serum amyloid A (SAA) and secretory phospholipase A2 (sPLA2), may contribute to the decrease in plasma HDLs. It has been suggested that HDLs possess anti-inflammatory properties and, hence, may play a crucial role in innate immunity by regulating the inflammatory response as well as being capable of reducing the severity of organ injury in animals and patients with septic shock. These protective effects of HDLs are mediated mainly via (a) lipopolysaccharide (LPS) binding and neutralization, (b) the HDL-associated enzymes, plasma paraoxonase (PON1) and platelet-activating factor acetylhydrolase (PAF-AH), which protect low-density lipoproteins against peroxidative damage, (c) inhibition of the expression of endothelial cell adhesion molecules and release of proinflammatory cytokines, which prevents inflammatory cell infiltration and subsequent multiple organ dysfunction, and (d) stimulation of the expression of endothelial nitric oxide synthase (eNOS). Thus, HDL exerts potent anti-inflammatory effects, some of which are independent of endotoxin binding and might be useful in the treatment of patients with not only sepsis/septic shock but also other conditions associated with an uncontrolled inflammatory response, such as ischemia-reperfusion injury and hemorrhagic shock. PMID:14770033

Wu, Aihua; Hinds, Charles J; Thiemermann, Christoph



Flow-cytometric determination of high-density-lipoprotein binding sites on human leukocytes  

SciTech Connect

In this method, leukocytes were isolated from 6 mL of EDTA-blood by density-gradient centrifugation and subsequently incubated with rhodamine isothiocyanate (RITC)-conjugated high-density lipoproteins (HDL). The receptor-bound conjugate particles were determined by fluorescent flow cytometry and compared with /sup 125/I-labeled HDL binding data for the same cells. Human granulocytes express the highest number of HDL binding sites (9.4 x 10(4)/cell), followed by monocytes (7.3 x 10(4)/cell) and lymphocytes (4.0 x 10(4)/cell). Compared with conventional analysis of binding of /sup 125/I-labeled HDL in tissue-culture dishes, the present determination revealed significantly lower values for nonspecific binding. In competition studies, the conjugate competes for the same binding sites as /sup 125/I-labeled HDL. With the use of tetranitromethane-treated HDL3, which fails to compete for the HDL receptor sites while nonspecific binding is not affected, we could clearly distinguish between 37 degrees C surface binding and specific 37 degrees C uptake of RITC-HDL3, confirming that the HDL receptor leads bound HDL particles into an intracellular pathway rather than acting as a docking type of receptor. Patients with familial dysbetalipoproteinemia showed a significantly higher number of HDL binding sites in the granulocyte population but normal in lymphocytes and monocytes, indicating increased uptake of cholesterol-containing lipoproteins. In patients with familial hypercholesterolemia, HDL binding was increased in all three cell types, indicating increased cholesterol uptake and increased cholesterol synthesis. The present method allows rapid determination of HDL binding sites in leukocytes from patients with various forms of hyper- and dyslipoproteinemias.

Schmitz, G.; Wulf, G.; Bruening, T.A.; Assmann, G.



Chitin-glucan fiber effects on oxidized low-density lipoprotein: a randomized controlled trial  

PubMed Central

Background/objectives: Elevated oxidized low-density lipoprotein (OxLDL) may promote inflammation, and is associated with increased risk of atherosclerotic coronary heart disease and worsening complications of diabetes mellitus. The primary objective of this study was to evaluate the efficacy of chitin-glucan (CG), alone and in combination with a potentially anti-inflammatory olive oil (OO) extract, for reducing OxLDL in subjects with borderline to high LDL cholesterol (LDL-C) levels. Subjects/methods: This 6-week, randomized, double-blind, placebo-controlled study of a novel, insoluble fiber derived from the Aspergillus niger mycelium, CG, evaluated 130 subjects free of diabetes mellitus with fasting LDL-C 3.37–4.92?mmol/l and glucose ?6.94?mmol/l. Participants were randomly assigned to receive CG (4.5?g/day; n=33), CG (1.5?g/day; n=32), CG (1.5?g/day) plus OO extract (135?mg/day; n=30), or matching placebo (n=35). Results: Administration of 4.5?g/day CG for 6 weeks significantly reduced OxLDL compared with placebo (P=0.035). At the end of study, CG was associated with lower LDL-C levels relative to placebo, although this difference was statistically significant only for the CG 1.5?g/day group (P=0.019). CG did not significantly affect high-density lipoprotein cholesterol, triglycerides, glucose, insulin or F2-isoprostane levels. Adverse events did not substantively differ between treatments and placebo. Conclusions: In this 6-week study, CG (4.5?g/day) reduced OxLDL, an effect that might affect the risk for atherosclerosis. PMID:22948945

Bays, H E; Evans, J L; Maki, K C; Evans, M; Maquet, V; Cooper, R; Anderson, J W



Effect of low-density lipoproteins on apolipoprotein AI kinetics in heterozygous familial hypercholesterolemia.  


In patients with heterozygous familial hypercholesterolemia (FH), both synthetic and clearance rates of high-density lipoproteins (HDL) are increased compared with control subjects. According to in vitro data on hepatocytes, the expanded pool size of low-density lipoproteins (LDL) in FH could partly explain the enhanced HDL production. Therefore, we have tested the hypothesis that a reduction of LDL pool size, achieved by LDL-apheresis, is associated with a downregulation of HDL synthesis. We studied the kinetics of HDL by infusing [5,5,5-(2)H(3)]-leucine in 7 heterozygous FH patients before and after 3 biweekly LDL-apheresis using dextran sulfate columns. Both plasma and LDL-cholesterol levels were decreased after LDL-apheresis (169 +/- 35 v 422 +/- 27 mg/dL, P <.05, and 85 +/- 19 v 327 +/- 52 mg/dL, P <.05, respectively). Plasma triglyceride level was unaffected (162 +/- 43 v 176 +/- 35 mg/dL, not significant [NS]) and HDL composition remained stable (HDL-cholesterol 29 +/- 6 v 37 +/- 7 mg/dL, NS, and HDL-triglyceride 20 +/- 6 v 19 +/- 8 mg/dL, NS). Plasma apolipoprotein AI (apo AI) was also similar (122 +/- 20 v 115 +/- 18 mg/dL, NS). Mean HDL-apo AI fractional catabolic rate (FCR) was slightly higher (0.41 +/- 0.07 v 0.36 +/- 0.14 pool/d, NS), and absolute production rate (APR) was increased (22.1 +/- 5.7 v 18.0 +/- 5.7 mg/kg/d, P <.05) after LDL-apheresis. These human kinetic data suggest that LDL do not play a major role on HDL production in heterozygous FH patients. PMID:11398137

Frénais, R; Maugeais, C; Ouguerram, K; Zaïr, Y; Bard, J M; Charbonnel, B; Magot, T; Krempf, M



Circulating Very-Low-Density Lipoprotein Characteristics Resulting from Fatty Liver in an Insulin Resistance Rat Model  

Microsoft Academic Search

The close association between nonalcoholic fatty liver and insulin resistance is now widely recognized. While the former is characterized by excessive intrahepatic triglyceride accumulation, the latter induces overproduction of very-low-density lipoprotein (VLDL) particles. It has not been well elucidated whether these apparently opposite mechanisms impact on VLDL characteristics or not. The aim of the present study was to evaluate the

V. Zago; D. Lucero; E. V. Macri; L. Cacciagiú; C. A. Gamba; V. Miksztowicz; G. Berg; R. Wikinski; S. Friedman; L. Schreier



Efficacy of Low-Density Lipoprotein Apheresis in Patients with Peripheral Arterial Occlusive Disease Undergoing Hemodialysis Treatment  

Microsoft Academic Search

Background: Low-density lipoprotein (LDL) apheresis is effective in the treatment of peripheral arterial occlusive disease (PAOD). In the present study, we attempted to determine whether LDL apheresis is effective even for PAOD patients undergoing hemodialysis, who tend to be refractory to any treatment, and if so, to determine the mechanism of its efficacy. Methods: Serum levels of lipids and vascular

Satoshi Morimoto; Yutaka Yano; Kei Maki; Katsunori Sawada; Toshiji Iwasaka



efficiently activates its G protein A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle  

E-print Network

efficiently activates its G protein A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle Brian Kobilka, and Roger K. Sunahara Matthew R. Whorton, Michael P. Bokoch, Søren G. F, see: Reprints To order reprints, see: Notes: #12;A monomeric G

Zare, Richard N.


Structural characterisation of nucleoside loaded low density lipoprotein as a main criterion for the applicability as drug  

E-print Network

to be developed. Human plasma low density lipoproteins (LDLs) are water-soluble nanoparticles which may.1016/S0009-3084(03)00002-1 #12;port vehicle of cholesterol and water-insoluble natural compounds, such as vitamins and hor- mones to various cell types (Esterbauer et al., 1992). The obvious idea to exploit

Hammel, Michal - School of Biological Sciences, University of Missouri


Hyperimmunization of apo-E-deficient mice with homologous malondialdehyde low-density lipoprotein suppresses early atherogenesis  

Microsoft Academic Search

The role of the immune system in modulating atherosclerosis has recently been the subject of intensive research. Several previous authors have put forward a paradigm of the autoimmune process occurring in the vicinity of the plaque. Two recent studies have shown that immunization of rabbits with homologous modified low-density lipoprotein (LDL) led to suppression of atherosclerosis. In the current study

Jacob George; Arnon Afek; Boris Gilburd; Hana Levkovitz; Aviv Shaish; Iris Goldberg; Yuri Kopolovic; Georg Wick; Yehuda Shoenfeld; Dror Harats



Identification of a deletion in the low density lipoprotein (LDL) receptor gene in a patient with familial hypercholesterolaemia  

Microsoft Academic Search

DNA samples from 60 unrelated UK patients with familial hypercholesterolaemia (FH) were screened by Southern blot hybridisation to detect gross alterations in the low density lipoprotein (LDL) receptor gene. One patient was found to have a 2kb deletion in the 3' part of the gene. The deletion cosegregates with the FH phenotype in his family. This finding is compatible with

B. Horsthemke; Anna M. Kessling; Mary Seed; V. Wynn; R. Williamson; S. E. Humphries



Effect of apolipoprotein E phenotype on diet-induced lowering of plasma low density lipoprotein cholesterol1  

Microsoft Academic Search

The National Cholesterol Education Program (NCEP) has recommended that dietary total fat, saturated fat, and cholesterol intake be reduced to 5 30% of calories, < 10% of calories, and < 300 mg\\/day, respectively (Step 1 diet) in the general population to reduce plasma low density lipoprotein (LDL) cholesterol levels and heart disease risk. We examined the LDL cholesterol-lowering response to

J. Lopez-Miranda; J. M. Ordovas; P. Mata; A. H. Lichtenstein; B. Clevidence; J. T. Judd; E. J. Schaefer


Effects of saturated and polyunsaturated fat diets on the chemical composition and metabolism of low density lipoproteins in man  

Microsoft Academic Search

This study examined the effects of dietary saturated and polyunsaturated fat on the chemical com- position and metabolism of low density lipoproteins (LDL) in eight normal male subjects. The influence of these diets on fecal sterol excretion was also measured in four of the subjects. When compared with the saturated fat diet, the polyunsaturated diet lowered both plasma cholesterol (2396,

James Shepherd; Christopher J. Packard; Scott M. Grundy; Daniel Yeshurun; Antonio M. Gotto; David Taunton


Effect of probucol dosage on plasma lipid and lipoprotein levels and on protection of low density lipoprotein against in vitro oxidation in humans.  


To determine whether probucol's ability to confer antioxidant protection to low density lipoprotein (LDL) could be dissociated from its ability to lower high density lipoprotein (HDL) cholesterol, 17 hypercholesterolemic patients were treated with either a standard dose, 1 g/day (4 tablets), or a low dose, 250 mg/day (1 tablet), of probucol for a 6-month period. Effects of therapy on lipoprotein levels and on susceptibility of LDL to in vitro oxidation were measured at frequent intervals. Probucol levels in plasma LDL rose less rapidly in the 1-tablet group but were nearly 50% of levels in the 4-tablet group after 6 months. HDL cholesterol and apolipoprotein A-1 decreased 17.6% and 27.9%, respectively, in the 1-tablet group compared with 28.0% and 38.3%, respectively, in the 4-tablet group (p = 0.07 and p = 0.06). In the 4-tablet group, LDL was protected from copper and endothelial cell-mediated oxidation after 2 months of therapy. In the 1-tablet group, equal degrees of protection occurred, but only after 6 months of therapy. In the whole study group, the decrease in LDL susceptibility to copper or endothelial cell-mediated oxidative modification was correlated with the content of probucol in LDL (r = 0.73, r = 0.65, p less than 0.005). Additionally, the decrease in HDL cholesterol level was correlated with the increase in protection to LDL from oxidative modification (r = 0.67 for copper, r = 0.58 for endothelial cells, p less than 0.05 for both) and also with the content of probucol in LDL (r = 0.6, p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1547191

Reaven, P D; Parthasarathy, S; Beltz, W F; Witztum, J L



Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management  

PubMed Central

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (?1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal. PMID:21531743

Chapman, M. John; Ginsberg, Henry N.; Amarenco, Pierre; Andreotti, Felicita; Boren, Jan; Catapano, Alberico L.; Descamps, Olivier S.; Fisher, Edward; Kovanen, Petri T.; Kuivenhoven, Jan Albert; Lesnik, Philippe; Masana, Luis; Nordestgaard, B?rge G.; Ray, Kausik K.; Reiner, Zeljko; Taskinen, Marja-Riitta; Tokgozoglu, Lale; Tybjaerg-Hansen, Anne; Watts, Gerald F.



PFOS induced lipid metabolism disturbances in BALB/c mice through inhibition of low density lipoproteins excretion  

NASA Astrophysics Data System (ADS)

Male BALB/c mice fed with either a regular or high fat diet were exposed to 0, 5 or 20 mg/kg perfluorooctane sulfonate (PFOS) for 14 days. Increased body weight, serum glucose, cholesterol and lipoprotein levels were observed in mice given a high fat diet. However, all PFOS-treated mice got reduced levels of serum lipid and lipoprotein. Decreasing liver glycogen content was also observed, accompanied by reduced serum glucose levels. Histological and ultrastructural examination detected more lipid droplets accumulated in hepatocytes after PFOS exposure. Moreover, transcripitonal activity of lipid metabolism related genes suggests that PFOS toxicity is probably unrelevant to PPAR?'s transcription. The present study demonstrates a lipid disturbance caused by PFOS and thus point to its role in inhibiting the secretion and normal function of low density lipoproteins.

Wang, Ling; Wang, Yu; Liang, Yong; Li, Jia; Liu, Yuchen; Zhang, Jie; Zhang, Aiqian; Fu, Jianjie; Jiang, Guibin



PFOS induced lipid metabolism disturbances in BALB/c mice through inhibition of low density lipoproteins excretion  

PubMed Central

Male BALB/c mice fed with either a regular or high fat diet were exposed to 0, 5 or 20?mg/kg perfluorooctane sulfonate (PFOS) for 14 days. Increased body weight, serum glucose, cholesterol and lipoprotein levels were observed in mice given a high fat diet. However, all PFOS-treated mice got reduced levels of serum lipid and lipoprotein. Decreasing liver glycogen content was also observed, accompanied by reduced serum glucose levels. Histological and ultrastructural examination detected more lipid droplets accumulated in hepatocytes after PFOS exposure. Moreover, transcripitonal activity of lipid metabolism related genes suggests that PFOS toxicity is probably unrelevant to PPAR?'s transcription. The present study demonstrates a lipid disturbance caused by PFOS and thus point to its role in inhibiting the secretion and normal function of low density lipoproteins. PMID:24694979

Wang, Ling; Wang, Yu; Liang, Yong; Li, Jia; Liu, Yuchen; Zhang, Jie; Zhang, Aiqian; Fu, Jianjie; Jiang, Guibin



A piezoelectric-based immunosensor for high density lipoprotein particle measurement.  


A piezoelectric-based immunosensor was developed for high density lipoprotein particle (HDL-P) measurement. Monoclonal anti-human apolipoprotein A1 antibody was used as a specific binding molecule for the major apolipoprotein of HDL-P. This sensing element was fabricated by immobilizing the anti-human apolipoprotein A1 on a 12 MHz AT-cut quartz crystal via a 3-mercaptopropionic acid (MPA) self-assembled monolayer. The frequency shift from the mass change of the antigen-antibody binding refers to the amount of HDL-P. The optimal antibody immobilization was performed to achieve the maximum potential of the antibody. The appropriate quantity and immobilization time of the antibody were 0.1 mg ml(-1) and 90 minutes, respectively. The immobilized antibody in the HDL-P immunosensor accomplished perfect binding with HDL-P within 60 minutes. The dose-response curve for HDL-P showed a linear response from 0.21 to 2.50 mg protein per ml equivalent to 0.40 × 10(10) to 3.65 × 10(10) particles per ?l without significant interference from other lipoproteins. The intra- and inter-assay imprecision (CV) were 7.8 and 18.5%, respectively. The analytical accuracy of this measurement was 96.29-96.31%. The HDL-P concentration obtained from the sensor revealed a 2.05 mg protein per ml with 0.26 mg protein per ml of expanded uncertainty at the 95% confidence level. This immunosensor gave an assay result which correlated with the homogeneous enzymatic colorimetric assay (R(2) = 0.902). PMID:25030774

Chunta, Suticha; Suk-Anake, Jamikorn; Chansiri, Kosum; Promptmas, Chamras



Effects of salt on the thermal stability of human plasma high-density lipoprotein.  


High-density lipoproteins (HDL) mediate cholesterol removal and thereby protect against atherosclerosis. Mature spherical HDL contain the apolar lipid core and polar surface of proteins and phospholipids. Earlier, we showed that the structural integrity of HDL is modulated by kinetic barriers that prevent spontaneous protein dissociation and lipoprotein fusion and rupture. To determine the role of electrostatic interactions in the kinetic stability of mature HDL, here we analyze the effects of salt and pH on their thermal denaturation. In low-salt buffer at pH 5.7-7.7, HDL are highly thermostable. Increasing the salt concentration from 0 to 0.3 M NaCl causes low-temperature shifts in the calorimetric HDL transitions of up to -14 degrees C. This salt-induced destabilization leads to protein unfolding below 100 degrees C, facilitating the first Arrhenius analysis of HDL denaturation by circular dichroism spectroscopy. In 150 mM NaCl, two kinetic phases in HDL protein unfolding are observed: a faster phase with an activation energy E(a,fast) < or =15 kcal/mol and a slower phase with an E(a,slow) = 50 +/- 7 kcal/mol. Gel electrophoresis and electron microscopic data suggest that the faster phase involves partial protein unfolding but no significant protein dissociation or changes in HDL size, while the slower phase involves complete protein unfolding, partial protein dissociation, and HDL fusion. Hence, the slower phase may resemble HDL remodeling and fusion by plasma enzymes during metabolism. Analysis of the effects of various salts, sucrose, and pH suggests that HDL destabilization by salt results from ionic screening of favorable short-range electrostatic interactions such as salt bridges. Consequently, electrostatic interactions significantly contribute to the high thermostability of HDL in low-salt solutions. PMID:16584197

Jayaraman, Shobini; Gantz, Donald L; Gursky, Olga



Oxidized Low Density Lipoprotein (LDL) Affects Hyaluronan Synthesis in Human Aortic Smooth Muscle Cells*  

PubMed Central

Thickening of the vessel in response to high low density lipoprotein(s) (LDL) levels is a hallmark of atherosclerosis, characterized by increased hyaluronan (HA) deposition in the neointima. Human native LDL trapped within the arterial wall undergoes modifications such as oxidation (oxLDL). The aim of our study is to elucidate the link between internalization of oxLDL and HA production in vitro, using human aortic smooth muscle cells. LDL were used at an effective protein concentration of 20–50 ?g/ml, which allowed 80% cell viability. HA content in the medium of untreated cells was 28.9 ± 3.7 nmol HA-disaccharide/cell and increased after oxLDL treatment to 53.9 ± 5.6. OxLDL treatments doubled the transcripts of HA synthase HAS2 and HAS3. Accumulated HA stimulated migration of aortic smooth muscle cells and monocyte adhesiveness to extracellular matrix. The effects induced by oxLDL were inhibited by blocking LOX-1 scavenger receptor with a specific antibody (10 ?g/ml). The cholesterol moiety of LDL has an important role in HA accumulation because cholesterol-free oxLDL failed to induce HA synthesis. Nevertheless, cholesterol-free oxLDL and unmodified cholesterol (20 ?g/ml) induce only HAS3 transcription, whereas 22,oxysterol affects both HAS2 and HAS3. Moreover, HA deposition was associated with higher expression of endoplasmic reticulum stress markers (CHOP and GRP78). Our data suggest that HA synthesis can be induced in response to specific oxidized sterol-related species delivered through oxLDL. PMID:23979132

Viola, Manuela; Bartolini, Barbara; Vigetti, Davide; Karousou, Evgenia; Moretto, Paola; Deleonibus, Sara; Sawamura, Tatsuya; Wight, Thomas N.; Hascall, Vincent C.; De Luca, Giancarlo; Passi, Alberto



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


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

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



Pharmacogenetic Predictors of Statin-Mediated Low-Density Lipoprotein Cholesterol Reduction and Dose Response  

PubMed Central

Background There is interindividual variation in low-density lipoprotein cholesterol (LDLc) lowering by statins and limited study into the genetic associations of the dose dependant LDLc lowering by statins. Methods and Results Five hundred nine patients with hyperlipidemia were randomly assigned atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg (low-dose phase) followed by 80 mg, 80 mg, and 40 mg (high-dose phase), respectively. Thirty-one genes in statin, cholesterol, and lipoprotein metabolism were sequenced and 489 single nucleotide polymorphisms with minor allele frequencies >2% were tested for associations with percentage LDLc lowering at low doses using multivariable adjusted general linear regression. Significant associations from the analysis at low dose were then repeated at high-dose statins. At low doses, only 1 single nucleotide polymorphism met our experiment-wide significance level, ABCA1 rs12003906. Twenty-six subjects carried the minor allele of rs12003906, which was associated with an attenuated LDLc reduction (LDLc reduction in carriers versus noncarriers ?24.1±2.6% versus ?32.2±1.5%; P=0.0001). In addition, we replicated the association with the APOE ?3 allele and a reduced LDLc reduction. At high doses, carriers of the minor allele of ABCA1 rs12003906 and the APOE ?3 allele improved their LDLc reduction but continued to have a diminished LDLc reduction compared with noncarriers (?30.5±4.0% versus ?42.0±2.4%; P=0.005) and (?38.5±1.9% versus ?45.3±2.8%; P=0.009), respectively. Conclusions An intronic single nucleotide polymorphism in ABCA1 and the APOE ?3 allele are associated with reduced LDLc lowering by statins and identify individuals who may be resistant to maximal LDLc lowering by statins. PMID:20031551

Voora, Deepak; Shah, Svati H.; Reed, Carol R.; Zhai, Jun; Crosslin, David R.; Messer, Chad; Salisbury, Benjamin A.; Ginsburg, Geoffrey S.



Effect of sphingomyelinase-mediated generation of ceramide on aggregation of low-density lipoprotein.  


This study addresses the response-to-retention hypothesis, which states that the subendothelial retention of atherogenic lipoproteins is the necessary and sufficient condition for the initiation of atherosclerosis. Here we focus on the relationship between the generation of ceramide in the low-density lipoprotein (LDL) phospholipid monolayer and the resulting aggregation of LDL particles. This study provides the first measurement of neutral, Mg (2+)-dependent Sphingomyelinase (Smase)-mediated ceramide formation from LDL-sphingomyelin and does so for a range of enzyme concentrations (0-0.22 units Smase/mL). The kinetics of ceramide generation was measured using a fluorescence assay for the above enzyme concentrations with a fixed substrate concentration (0.33 mg LDL/mL). The kinetics of LDL aggregate formation was measured by dynamic light scattering (DLS, method of cumulants) for identical enzyme concentrations. Ceramide concentration profiles were fit with a modification of the Michaelis-Menten model ( k a = 1.11 x 10 (-1) microM (-1) min (-1), k -a = 6.54 x 10 (2) microM (-1) min (-1), k 1 = 3.33 x 10 (1) microM (-1) min (-1), k -1 = 1.41 x 10 (-2) min (-1), k cat = 8.05 x 10 (1) min (-1), K M = 2.418 microM, k deact = 4.66 x 10 (-2) microM (-1) min (-1)) that accounts for the effects of enzyme attachment to the LDL monolayer and for deactivation of Smase due to product inhibition. LDL aggregation is described by a mass action model as explained in previous studies. A key result of this work is the finding that LDL aggregate size depends directly on ceramide concentration and is independent of enzyme concentration. This study demonstrates how principles of colloid science are relevant to important biomedical problems. PMID:18671414

Walters, Michael J; Wrenn, Steven P



Compositional or charge density modification of the endothelial glycocalyx accelerates flow-dependent concentration polarization of low-density lipoproteins.  


We hypothesized that diminished endothelial glycocalyx (GCX) at atherosclerotic lesion-prone sites accelerates flow-dependent concentration polarization of low-density lipoproteins (LDLs) at the luminal surface, and in turn contributes to vulnerability of these sites to atherosclerosis. A parallel plate flow chamber was applied to expose cultured endothelial monolayers to three different levels of shear stress (3, 12, 20 dyn/cm(2)). Heparinase III (Hep.III) was employed to degrade heparan sulfate proteoglycans selectively and 3-(N-morpholino) propanesulfonic acid-buffered physiological salt solutions (MOPS-PSS) were used at either normal ionic strength (Normal-MOPS), low ionic strength (LO-MOPS) or high ionic strength (HI-MOPS) to modify the effective charge density of the endothelial GCX. Water filtration velocity (V(w)) across the endothelial monolayer, the luminal concentration of LDLs (C(w)) and the uptake of LDLs by endothelial cells were measured and compared among the following five groups of cells: (1) Control; (2) Hep.III treatment; (3) LO-MOPS; (4) Normal-MOPS; and (5) HI-MOPS. The results obtained substantiated the aforementioned hypothesis and demonstrated that compositional or charge density modification of the endothelial GCX facilitated water filtration across the endothelium, enhanced the accumulation of LDLs on the luminal surface and increased the uptake of LDLs by endothelial cells, therefore contributing to atherogenesis. PMID:21659384

Kang, Hongyan; Fan, Yubo; Sun, Anqiang; Deng, Xiaoyan



Lipoprotein receptors in copper-deficient rats: in vitro binding of high-density lipoprotein subfractions to liver membranes  

SciTech Connect

Three studies were conducted to determine whether the elevated plasma and HDL cholesterol levels observed in copper-deficient rats could be explained by the interaction of /sup 125/I-HDL subfractions with liver membrane preparations in vitro. Rats from all studies were randomly divided into two dietary treatments, copper-deficient and adequate (0.7 mg and 8.0 mg Cukg diet, respectively). Total binding data and computer derived estimates (K/sub d/ and B/sub max/) were used to compare differences between treatments. Binding data from all experiments conformed to a one-site model. In all cases, binding was saturable and EDTA and pronase insensitive. Treatment differences were observed in Study I (/sup 125/I-apo E-free HDL binding to crude liver membranes). Significantly lower total binding and B/sub max/ were observed when lipoproteins and membranes from copper-deficient animals were used in the assay. Competition experiments from Studies II and III demonstrate that the different HDL subfractions competed effectively with one another for binding sites, indicating that apo E is not a determinant in binding of rat /sup 125/I-HDL subfractions to purified liver plasma membranes

Hassel, C.A.



Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma.  

PubMed Central

Many reactive products may be formed when LDL undergoes lipid peroxidation, which in turn can react with lipids, apoproteins, and proteins, generating immunogenic neoepitopes. Autoantibodies recognizing model epitopes of oxidized low density lipoprotein, such as malondialdehydelysine, occur in plasma and in atherosclerotic lesions of humans and animals. Because apo E-deficient mice develop particularly high titers of such autoantibodies, we used their spleens to clone 13 monoclonal antibodies to various epitopes of oxidized LDL ("E0 antibodies"). Binding and competitive RIAs demonstrated significant differences in fine specificity even between E0 antibodies initially selected for binding to the same screening antigen. For example, some E0 antibodies selected for binding to malondialdehyde-LDL also recognized copper oxidized LDL, acrolein-LDL, or LDL modified by arachidonic or linoleic acid oxidation products. Circulating IgG and IgM autoantibodies binding to copper-oxidized LDL, 4-hydroxynonenal-LDL, acrolein-LDL, and LDL modified with arachidonic or linoleic acid oxidation products were found in apo E-deficient mice, suggesting that the respective antigens are formed in vivo. Epitopes recognized by some of the E0 monoclonal antibodies were also found on human circulating LDL. Each of the E0 monoclonal antibodies immunostained rabbit and human atherosclerotic lesions, and some of them yielded distinct staining patterns in advanced lesions. Together, this suggests that the natural monoclonal antibodies recognize different epitopes of complex structures formed during oxidation of lipoproteins, or epitopes formed independently at different lesion sites. Our data demonstrate that a profound immunological response to a large number of different epitopes of oxidized lipoproteins occurs in vivo. The availability of "natural" monoclonal autoantibodies should facilitate the identification of specific epitopes inducing this response. PMID:8698873

Palinski, W; Horkko, S; Miller, E; Steinbrecher, U P; Powell, H C; Curtiss, L K; Witztum, J L



Possible role of the Golgi apparatus in the assembly of very low density lipoprotein  

SciTech Connect

Transit of newly synthesized triacyl(3H)-glycerol through organelles of the secretory system leading to assembly into nascent very low density lipoproteins (VLDLs) or to cytoplasmic storage was investigated in chick hepatocytes. Cells in monolayer culture were pulse-labeled with (2-3H)glycerol, and after different periods of chase with unlabeled glycerol, the movement of triacyl(3H)glycerol through the endoplasmic reticulum (ER) and Golgi and the incorporation into nascent VLDL and cytoplasmic triacylglycerol-rich vesicles (TGRVs) were determined. Initially, newly synthesized triacyl(3H)glycerol is tightly associated with the ER. Movement from the ER of triacyl(3H)glycerol destined for cytoplasmic storage (as TGRVs) is extremely rapid and virtually complete within 8 min of chase. After 8 min of chase, triacyl(3H)glycerol lost from organelles of the secretory system was accounted for entirely as triacyl(3H)glycerol secreted as VLDL. Comparison of the rates of movement of triacyl(3H)glycerol, apolipoprotein B, apolipoprotein II, and apolipoprotein A-I through the ER and Golgi and of their secretion in nascent VLDL suggests that assembly of triacyglycerol with apolipoproteins occurs in the Golgi. Experiments with permeabilized hepatocytes supplemented with cytosol show that newly synthesized triacyl(3H)glycerol and (3H)phospholipid moves from the ER through the full-density range of Golgi elements and is dependent upon supplementary ATP.

Bamberger, M.J.; Lane, M.D. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (USA))



Application of High-Sensitivity Reagent to the Dade Dimension XL for the Determination of Cholesterol in High-Density and Low-Density Lipoprotein Serum Fractions  

Microsoft Academic Search

We have applied a reagent for the determination of cholesterol in high- and low-density lipoprotein (HDL and LDL) fractions to the Dade Dimension XL automated chemistry analyzer. This reagent has an inherent sensitivity that is four times greater than those of the more common reagents that use phenol or hydroxybenzoate in their indicator reaction. The enhanced sensitivity resulting from the

Joseph D. Artiss; Edward Capellari; G. Russell Warnick; Bennie Zak



Thyroid hormone increases plasma cholesteryl ester transfer protein activity and plasma high-density lipoprotein removal rate in transgenic mice.  


Thyroid dysfunction produces multiple alterations in plasma lipoprotein levels, including high-density lipoprotein (HDL). Cholesteryl ester transfer protein (CETP) and hepatic lipase (HL) are important proteins that modulate the metabolism of HDL. Thus, the effect of thyroid hormone on the activities of CETP and of HL was investigated using hypothyroid and hyperthyroid CETP transgenic (Tg) and nontransgenic (nTg) mice. Hyperthyroid Tg mice plasma lipoprotein (LP) profile analysis showed a significant increase in the very-low-density lipoprotein (VLDL) fraction (P <.001) and decrease in the HDL fraction (P <.005), whereas in the hypothyroid Tg mice an increase in low-density lipoprotein (LDL) was observed (P <.02). CETP activity was measured as the transfer of (14)C-cholesteryl ester (CE) from labeled HDL to LDL by an isotopic assay indicative of mass. Hyperthyroid Tg mice had twice as much plasma CETP activity as compared with their controls, while in hypothyroid Tg mice plasma CETP activity did not change. The role of CETP in determining the changes in LP profile of hyperthyroid animals was confirmed by showing that nTg wild-type hyperthyroid and euthyroid mice exhibited the same percent cholesterol distribution in LP. Postheparin HL activity measured in hyperthyroid Tg mice was significantly reduced (P <.05). (3)H-cholesteryl oleoyl ether ((3)H-Cet)-HDL plasma fractional removal rate (FRR) was approximately 2-fold faster in the hyperthyroid Tg mice than in controls, but was not modified in hypothyroid animals. Tissue uptake of (3)H-Cet was examined in 10 tissue samples: levels were significantly increased in skeletal muscle and decreased in small intestine in hyperthyroid Tg mice, and decreased in the small intestine of hypothyroid Tg mice. In conclusion, the excess of thyroid hormone accelerates HDL metabolism in CETP transgenic mice mainly due to an increase in plasma CETP activity and independently from the HL activity. Hypothyroid status did not change CETP activity and HDL metabolism. PMID:11319713

Berti, J A; Amaral, M E; Boschero, A C; Nunes, V S; Harada, L M; Castilho, L N; Oliveira, H C



Modeling of Corticosteroid Effects on Hepatic Low-Density Lipoprotein Receptors and Plasma Lipid Dynamics in Rats  

PubMed Central

Purpose This study examines methylprednisolone (MPL) effects on the dynamics of hepatic low-density lipoprotein receptor (LDLR) mRNA and plasma lipids associated with increased risks for atherosclerosis. Materials and methods Normal male Wistar rats were given 50 mg/kg MPL intramuscularly (IM) and sacrificed at various times. Measurements included plasma MPL and CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density and hepatic LDLR mRNA, and plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), and triglycerides (TG). Results MPL showed bi-exponential disposition with two first-order absorption components. Hepatic GR and LDLR mRNA exhibited circadian patterns which were disrupted by MPL. Down-regulation in GR mRNA (40–50%) was followed by a delayed rebound phase. LDLR mRNA exhibited transient down-regulation (60–70%). Cytosolic GR density was significantly suppressed but returned to baseline by 72 h. Plasma TC and LDLC showed increases (55 and 142%) at 12 h. A mechanistic receptor/gene pharmacokinetic/pharmacodynamic model was developed to describe CS effects on hepatic LDLR mRNA and plasma cholesterols. Conclusions Our PK/PD model was able to satisfactorily capture the MPL effects on hepatic LDLR, its relationship to various plasma cholesterols, and builds the foundation to explore this area in the future. PMID:17674160

Hazra, Anasuya; Pyszczynski, Nancy A.; DuBois, Debra C.; Almon, Richard R.



Changes in low-density lipoprotein electronegativity and oxidizability after aerobic exercise are related to the increase in associated non-esterified fatty acids  

Microsoft Academic Search

The immediate effects of intense aerobic exercise on the composition and oxidizability of low- (LDL) and high-density lipoproteins (HDL) were studied in 11 male athletes. Plasma parameters known to affect lipoprotein oxidizability were also evaluated. Lipophilic antioxidants, including ?-tocopherol and carotenoids, paraoxonase and malondialdehyde (MDA) in plasma remained unchanged after exercise. Increases in the concentration of uric acid, bilirubin and

Sonia Ben??tez; José Luis Sánchez-Quesada; Liliana Lucero; Rosa Arcelus; Vicent Ribas; Oscar Jorba; Agustina Castellv??; Esther Alonso; Francisco Blanco-Vaca; Jordi Ordóñez-Llanos



A study of the abnormal lipoproteins in abetalipoproteinemia.  

PubMed Central

The serum lipoproteins of five patients with abetalipoproteinemia (ABL) were separated by ultracentrifugation and then analyzed either intact or after delipidation. In accord with previous findings, all of the patients lacked serum particles with the characteristics of normal low-density lipoproteins (LDL) and of the LDL apoprotein as assessed by immunochemical methods. Each patient exhibited on every examination an abnormal particle, "LDL", which had the flotational properties of LDL, the polypeptide makeup of high-density lipoproteins HDL, the spectral and morphological characteristics of neither LDL nor HDL, and a relatively low content of cholesteryl esters. The HDL were abnormal in having a marked decrease in their total plasma content, an altered proportion of the subclasses HDL2 and HDL3, and a peculiar polypeptide distribution, comprising both normal and additional components, usually not seen in normal controls. The patients also exhibited a decrease of plasma lecithin-cholesterol acyl transferase (LCAT) activity which probably accounted for the low content of cholesteryl esters in both "LDL" and HDL, and in turn for the unusual appearance of "LDL" on electron microscopy. It is concluded that ABL is a disorder affecting all serum lipoprotein classes. Whether the abetalipoproteinemia previously described and noted in the current studies is related to or independent of the abnormalities observed in the other lipoproteins was not established. How the deficiency of LCAT activity, observed in all patients studied, contributed to some of the observed structural lipoprotein abnormalities also remained undetermined. Images PMID:11344558

Scanu, A M; Aggerbeck, L P; Kruski, A W; Lim, C T; Kayden, H J



Apolipoprotein A-1 predicts coronary heart disease only at low concentrations of high-density lipoprotein cholesterol: an epidemiological study of Japanese-Americans  

Microsoft Academic Search

Conventional epidemiological and clinical studies of apolipoprotein A-1 and high-density lipoprotein-cholesterol have demonstrated,\\u000a when examined jointly, that high-density lipoprotein is a better predictor of coronary heart disease. This strategy does not\\u000a take into account known lipid metabolic relationships. A statistical approach that takes into account apoliprotein A-1 being\\u000a a constituent of the high-density lipoprotein particle is more appropriate. Among 1,177

D. S. Sharp; C. M. Burchfiel; B. L. Rodriguez; A. R. Sharrett; P. D. Sorlie; S. M. Marcovina



Effects of Fluvastatin on Plasma Levels of Low-Density Lipoprotein Subfractions, Oxidized Low-Density Lipoprotein, and Soluble Adhesion Molecules: A Twenty-Four–Week, Open-Label, Dose-Increasing Study  

Microsoft Academic Search

Background: Statins not only lower low-density lipoprotein (LDL) levels, but also have several antiarteriosclerotic effects (eg, decreasing arterial inflammation and arterial smooth muscle cell proliferation, as well as antioxidant effects). The relationship between the dose of statin and its effects on plasma LDL levels and other arteriosclerosis-related effects remains to be clarified.Objective: We investigated the effect of a statin, fluvastatin,

Yasuhiko Homma; Koichiro Homma; Shinichi Iizuka; Kamon Iigaya



High-density lipoprotein-associated 17?-estradiol fatty acyl ester uptake by Fu5AH hepatoma cells: Implications of the roles of scavenger receptor class B, type I and the low-density lipoprotein receptor  

Microsoft Academic Search

17?-Estradiol (E2) fatty acyl esters naturally incorporate into high-density lipoprotein (HDL). The objective was to elucidate mechanisms involved in HDL-associated E2 cellular uptake and to determine the intracellular distribution of E2 and its fatty acyl esters (E2-FAE) after uptake. [3H]E2 or [3H] cholesterol was incubated with human serum for 24 h to allow for fatty acyl esterification. Total-HDL containing [3H]E2-FAE or

Robert M. Badeau; Jari Metso; Matti J. Tikkanen; Matti Jauhiainen



Interactions between sphingomyelin and cholesterol in low density lipoproteins and model membranes.  


This work examines three related, but previously unexplored, aspects of membrane biophysics and colloid science in the context of atherosclerosis. First, we show that sphingomyelinase (SMase)-induced aggregation of low density lipoproteins (LDLs), coupled with LDL exposure to cholesterol esterase (CEase), results in nucleation of cholesterol crystals, long considered the hallmark of atherosclerosis. In particular, this study reveals that the order of enzyme addition does not effect the propensity of LDL to nucleate cholesterol crystals, raising the possibility that nucleation can proceed from either the intra- or extracellular space. Second, we demonstrate that ceramide-rich aggregates of LDL release cholesterol to neighboring vesicles far more rapidly, and to a greater extent, than does native LDL. A likely explanation for this observation is displacement of cholesterol from SM-Chol rafts by "raft-loving" ceramide. Third, we demonstrate that a time-independent Förster resonance energy transfer (FRET) assay, based on dehydroergosterol and dansylated lecithin and used previously to study cholesterol nanodomains, can be used to measure raft sizes (on the order of 10 nm) in model membrane systems. Taken together, these observations point to the possibility of an extracellular nucleation mechanism and underscore the important role that biological colloids play in human disease. PMID:16019021

Guarino, Andrew J; Lee, Sum P; Wrenn, Steven P



High-density lipoprotein composition in obesity: interrelationships with plasma insulin levels and body weight.  


Hyperinsulinism may play a role in the development of atherosclerosis. In this study we analyzed the interrelationships between plasma glucose, insulin, body weight and high-density lipoproteins (HDL) in a group of obese women and faced the question of what is the effect of obesity on insulin, glucose and HDL relationships. HDL cholesterol was significantly lower, while HDL triglycerides resulted significantly higher in the obese women than in the controls. The two groups did not show any difference in the serum concentration of HDL apoprotein A-I and apoprotein A-II. There was an inverse correlation between fasting plasma glucose and summated means of glucose and insulin levels after an oral glucose tolerance test and HDL cholesterol in the two groups; on the contrary a positive relationship between the same parameters and HDL triglyceride occurred. HDL cholesterol was inversely related also to the weight index, while HDL triglyceride concentration was directly correlated with this parameter in the two groups. Partial correlation analysis demonstrates that, when exposed to similar plasma insulin and glucose levels, HDL cholesterol and triglyceride concentrations were no longer correlated with the weight index, and therefore that the significant correlations between these variables are likely to be due to the significant correlations of each of them with plasma glucose and insulin levels. Further studies clarifying the role of glucose and insulin in determining HDL composition would appear important. PMID:3058617

Cominacini, L; Zocca, I; Garbin, U; Davoli, A; Micciolo, R; De Bastiani, P; Bosello, O



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

SciTech Connect

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.

Fielding, P.E.; Miida, Takashi; Fielding, C.J. (Univ. of California, San Francisco (United States))



Differential binding preference of methylpheophorbide a and its diboronated derivatives to albumin and low density lipoproteins.  


The tetrapyrrolic macrocycle and the functional groups at its periphery allow for a variety of modifications aimed at multifunctional therapeutic compounds. In particular, conjugation of boron polyhedra yields dual efficacy antitumor photo/ radiosensitizers. Structural optimization of these agents presumes the identification of macromolecules that bind and transport boronated tetrapyrroles. Using spectroscopic methods we demonstrated that methylpheophorbide a forms complexes with serum albumin and low density lipoproteins (LDL) whereas two diboronated derivatives, 13(2),17(3)-[di(o-carboran-1-yl)methoxycarbonyl]pheophorbide a and 13(2),17(3)-[di(1-carba-closo-dodecaboran-1-yl)methoxycarbonyl]pheophorbide a, were capable of binding to LDL but not to albumin. Molecular modeling showed a mode of interaction of methylpheophorbide a with the amino acid residues in the albumin's hemin binding site. In contrast, for diboronated derivatives such interactions are sterically hindered by boron polyhedra, in line with experimentally determined lack of complex formation with albumin. These data strongly suggest that LDL might be the preferred carrier for polycarborane containing methylpheophorbide a derivatives. PMID:23343083

Golovina, Galina V; Rychkov, Georgy N; Ol'shevskaya, Valentina A; Zaitsev, Andrei V; Kalinin, Valery N; Kuzmin, Vladimir A; Shtil, Alexander A



Anti-psoriatic therapy recovers high-density lipoprotein composition and function.  


Psoriasis is a chronic inflammatory disorder associated with increased cardiovascular mortality. Psoriasis affects high-density lipoprotein (HDL) composition, generating dysfunctional HDL particles. However, data regarding the impact of anti-psoriatic therapy on HDL composition and function are not available. HDL was isolated from 15 psoriatic patients at baseline and after effective topical and/or systemic anti-psoriatic therapy and from 15 age- and sex-matched healthy controls. HDL from psoriatic patients showed a significantly impaired capability to mobilize cholesterol from macrophages (6.4 vs. 8.0% [(3)H]cholesterol efflux, P<0.001), low paraoxonase (217 vs. 350??M(-1)?minute(-1)?mg(-1) protein, P=0.011) and increased Lp-PLA2 activities (19.9 vs. 12.1?nM(-1)?minute(-1)?mg(-1) protein, P=0.028). Of particular interest, the anti-psoriatic therapy significantly improved serum lecithin-cholesterol acyltransferase activity and decreased total serum lipolytic activity but did not affect serum levels of HDL-cholesterol. Most importantly, these changes were associated with a significantly improved HDL-cholesterol efflux capability. Our results provide evidence that effective anti-psoriatic therapy recovers HDL composition and function, independent of serum HDL-cholesterol levels, and support to the emerging concept that HDL function may be a better marker of cardiovascular risk than HDL-cholesterol levels. PMID:23985995

Holzer, Michael; Wolf, Peter; Inzinger, Martin; Trieb, Markus; Curcic, Sanja; Pasterk, Lisa; Weger, Wolfgang; Heinemann, Akos; Marsche, Gunther



Structure of apolipoprotein A-I in spherical high density lipoproteins of different sizes  

PubMed Central

Spherical high density lipoproteins (HDL)† predominate in human plasma. However, little information exists on the structure of the most common HDL protein, apolipoprotein (apo) A-I, in spheres vs. better studied discoidal forms. We produced spherical HDL by incubating reconstituted discoidal HDL with physiological plasma-remodeling enzymes and compared apoA-I structure in discs and spheres of comparable diameter (79–80 and 93–96 ?). Using cross-linking chemistry and mass spectrometry, we determined that the general structural organization of apoA-I was overall similar between discs and spheres, regardless of diameter. This was the case despite the fact that the 93 ? spheres contained three molecules of apoA-I per particle compared with only two in the discs. Thus, apoA-I adopts a consistent general structural framework in HDL particles—irrespective of shape, size and the number of apoA-Is present. Furthermore, a similar cross-linking pattern was demonstrated in HDL particles isolated from human serum. We propose the first experiment-based molecular model of apoA-I in spherical HDL particles. This model provides a new foundation for understanding how apoA-I structure modulates HDL function and metabolism. PMID:18719128

Silva, R. A. Gangani D.; Huang, Rong; Morris, Jamie; Fang, Jianwen; Gracheva, Elena O.; Ren, Gang; Kontush, Anatol; Jerome, W. Gray; Rye, Kerry-Anne; Davidson, W. Sean



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

PubMed Central

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

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



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

NASA Astrophysics Data System (ADS)

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

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



Education, race, and high-density lipoprotein cholesterol among US adults.  

PubMed Central

OBJECTIVES. Although educational achievement is positively related to levels of high-density lipoprotein cholesterol (HDL-C) among White adults, there is an inverse association among Blacks. We assessed whether this interaction could be attributed to differences in the relation of education to correlates of HDL-C. METHODS. Cross-sectional analyses were based on data from 8391 White and 995 Black adults who participated in the Second National Health and Nutrition Examination Survey. RESULTS. Associations between education and HDL-C levels varied from negative (Black men), to nearly nonexistent (White men and Black women), to positive (White women). Mean HDL-C levels were higher among Blacks than among Whites, but differences varied according to educational achievement. Among adults with less than 9 years of education, mean levels were 6 to 10 mg/dL higher among Blacks, but the radical difference was less than 1 mg/dL among adults with at least 16 years of education. About 20% to 40% of these differences could be accounted for by obesity, alcohol consumption, and other characteristics. CONCLUSIONS. Because of the implications for coronary heart disease risk, consideration should be given to behavioral characteristics associated with the interaction between race and educational achievement. PMID:1609919

Freedman, D S; Strogatz, D S; Williamson, D F; Aubert, R E



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

SciTech Connect

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

Albrink, M.J. (West Virgina Unov., Morgantown); Krauss, R.M.; Lindgren, F.T.; von der Groeben, J.; Pan, S.; Wood, P.D.



Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis  

PubMed Central

Immune responses to oxidized low-density lipoprotein (oxLDL) are proposed to be important in atherosclerosis. To identify the mechanisms of recognition that govern T cell responses to LDL particles, we generated T cell hybridomas from human ApoB100 transgenic (huB100tg) mice that were immunized with human oxLDL. Surprisingly, none of the hybridomas responded to oxidized LDL, only to native LDL and the purified LDL apolipoprotein ApoB100. However, sera from immunized mice contained IgG antibodies to oxLDL, suggesting that T cell responses to native ApoB100 help B cells making antibodies to oxLDL. ApoB100 responding CD4+ T cell hybridomas were MHC class II–restricted and expressed a single T cell receptor (TCR) variable (V) ? chain, TRBV31, with different V? chains. Immunization of huB100tgxLdlr?/? mice with a TRBV31-derived peptide induced anti-TRBV31 antibodies that blocked T cell recognition of ApoB100. This treatment significantly reduced atherosclerosis by 65%, with a concomitant reduction of macrophage infiltration and MHC class II expression in lesions. In conclusion, CD4+ T cells recognize epitopes on native ApoB100 protein, this response is associated with a limited set of clonotypic TCRs, and blocking TCR-dependent antigen recognition by these T cells protects against atherosclerosis. PMID:20439543

Hermansson, Andreas; Ketelhuth, Daniel F.J.; Strodthoff, Daniela; Wurm, Marion; Hansson, Emil M.; Nicoletti, Antonino; Paulsson-Berne, Gabrielle



High Density Lipoprotein Nanoparticles Deliver RNAi to Endothelial Cells to Inhibit Angiogenesis  

PubMed Central

Systemic delivery of therapeutic nucleic acids to target cells and tissues outside of the liver remains a major challenge. We synthesized a biomimetic high density lipoprotein nanoparticle (HDL NP) for delivery of a cholesteryl modified therapeutic nucleic acid (RNAi) to vascular endothelial cells, a cell type naturally targeted by HDL. HDL NPs adsorb cholesteryl modified oligonucleotides and protect them from nuclease degradation. As proof of principle, we delivered RNAi targeting vascular endothelial growth factor receptor 2 (VEGFR2) to endothelial cells to effectively silence target mRNA and protein expression in vitro. In addition, data show that treatment strongly attenuated in vivo neovascularization measured using a standard angiogenesis assay and in hypervascular tumor allografts where a striking reduction in tumor growth was observed. For effective delivery, HDL NPs required the expression of the cell surface protein scavenger receptor type-B1 (SR-B1). No toxicity of HDL NPs was measured in vitro or after in vivo administration. Thus, by using a biomimetic approach to nucleic acid delivery, data demonstrate that systemically administered RNAi-HDL NPs target SR-B1 expressing endothelial cells to deliver functional anti-angiogenic RNAi as a potential treatment of cancer and other neo-vascular diseases.

Tripathy, Sushant; Vinokour, Elena; McMahon, Kaylin M.; Volpert, Olga V.; Thaxton, C. Shad



Low high-density lipoprotein cholesterol is characterized by elevated oxidative stress.  


High-density lipoprotein cholesterol (HDL-C) is an independent risk factor for premature atherosclerosis and cardiovascular disease. Plasma HDL exerts potent antioxidant activity. We evaluated parameters associated with oxidative stress in participants with low HDL-C. This study included 32 patients with low HDL-C (?35 mg/dL) and 33 age- and sex-matched control patients with normal HDL-C (>35 mg/dL). We evaluated clinical and laboratory parameters that are associated with oxidative stress. The oxidative stress index (OSI) levels were significantly higher in the low HDL-C group (3.32 [0.01-13.3] vs 0.74 [0.17-3.55] AU; P < .01) and negatively correlated with HDL-C levels. We suggest that change in OSI and uric acid levels in the study group might indicate increased oxidative status in patients with low HDL-C. This may be associated with increased cardiovascular risk. PMID:24280265

Karabacak, Mustafa; Varol, Ercan; Kahraman, Fatih; Ozaydin, Mehmet; Türkdogan, Ahmet Kenan; Ersoy, Ismail Hakk?



Ordering and stability in lipid droplets with applications to low-density lipoproteins  

NASA Astrophysics Data System (ADS)

In this article, we present a framework for investigating the order-disorder transition in lipid droplets using the standard Ising model. While a single lipid droplet is itself a complex system whose constituent cholesteryl esters each possesses many degrees of freedom, we present justification for using this effective approach to isolate the underlying physics. It is argued that the behavior of the esters confined within lipid droplets is significantly different from that of a bulk system of similar esters, which is adequately described by continuum mean-field theory in the thermodynamic limit. When the droplet's shell is modeled as an elastic membrane, a simple picture emerges for a transition between two ordered phases within the core which is tuned by the strength of interactions between the esters. Triglyceride concentration is proposed as a variable which strongly influences the strength of interactions between cholesteryl esters within droplets. The possible relevance of this mechanism to the well known atherogenic nature of small low-density lipoprotein particles is discussed in detail.

Lancaster, Jarrett L.; Antonijevic, Todor; Starobin, Joseph M.



In vitro oxidative footprinting provides insight into apolipoprotein B-100 structure in low-density lipoprotein.  


Low-density lipoprotein (LDL) is a major cholesterol carrier in human blood. Oxidations of apolipoprotein B-100 (apo B-100, LDL protein) could be proatherogenic and play critical roles in early stages of plaque formation in the arterial wall. The structure of apo B-100 is still poorly understood, partially due to its size (550 KDa, 4563 amino acids). To gain an insight into LDL structure, we mapped the regions of apo B-100 in human LDL that were prone to oxidation using peroxynitrite and hypochlorite as probes. In this study, LDL was incubated with various concentrations of peroxynitrite and sodium hypochlorite in bicarbonate buffer. The LDL protein apo B-100 was delipidated, denatured, alkylated, and subjected to tryptic digestion. Tryptic peptides were analyzed employing LC-MS/MS. Database search was performed against the apo B-100 database (SwissProt accession #P04114) using "SEQUEST" algorithm to identify peroxynitrite and hypochlorite-mediated oxidations markers nitrotyrosine, nitrotryptophan, hydroxy-tryptophan, and 3-chlorotyrosine. Several site-specific oxidations were identified in apo B-100 after treatment of intact LDL particles with the oxidants. We hypothesize that these regions could be accessible to oxidant and critical for early events in atherosclerotic plaque deposition. PMID:25176030

Chakraborty, Sourav; Cai, Yang; Tarr, Matthew A



Role of the Low-Density Lipoprotein Receptor in Entry of Bovine Viral Diarrhea Virus?  

PubMed Central

Among several proposed cellular receptors for bovine viral diarrhea virus (BVDV), the low-density lipoprotein (LDL) receptor is of special interest because it is also considered a receptor for the related hepatitis C virus. It has been reported that an anti-LDL receptor monoclonal antibody blocked the infection of bovine cells by BVDV and that the resistance of bovine CRIB cells (cells resistant to infection with BVDV) (E. F. Flores and R. O. Donis, Virology 208:565-575, 1995) to BVDV infection was due to a lack of the LDL receptor (V. Agnello et al., Proc. Natl. Acad. Sci. USA 96:12766-12771, 1999). In connection with our studies on BVDV entry, we reevaluated the putative role of the LDL receptor as a cellular receptor for BVDV. It was first clearly demonstrated that neither of two monoclonal antibodies against the LDL receptor inhibited BVDV infection of two bovine cell lines. Furthermore, the LDL receptor was detected on the surface of CRIB cells. The functionality of the LDL receptor on CRIB cells was demonstrated by the internalization of fluorescently labeled LDL. In conclusion, at present no experimental evidence supports an involvement of the LDL receptor in BVDV invasion. PMID:16928760

Krey, Thomas; Moussay, Etienne; Thiel, Heinz-Jürgen; Rümenapf, Till



A Systems Genetic Analysis of High Density Lipoprotein Metabolism and Network Preservation across Mouse Models  

PubMed Central

We report a systems genetics analysis of high density lipoproteins (HDL) levels in an F2 intercross between inbred strains CAST/EiJ and C57BL/6J. We previously showed that there are dramatic differences in HDL metabolism in a cross between these strains, and we now report co-expression network analysis of HDL that integrates global expression data from liver and adipose with relevant metabolic traits. Using data from a total of 293 F2 intercross mice, we constructed weighted gene co-expression networks and identified modules (subnetworks) associated with HDL and clinical traits. These were examined for genes implicated in HDL levels based on large human genome-wide associations studies (GWAS) and examined with respect to conservation between tissue and sexes in a total of 9 data sets. We identify genes that are consistently ranked high by association with HDL across the 9 data sets. We focus in particular on two genes, Wfdc2 and Hdac3, that are located in close proximity to HDL QTL peaks where causal testing indicates that they may affect HDL. Our results provide a rich resource for studies of complex metabolic interactions involving HDL. PMID:21807117

Langfelder, Peter; Castellani, Lawrence W.; Zhou, Zhiqiang; Paul, Eric; Davis, Richard; Schadt, Eric E.; Lusis, Aldons J.; Horvath, Steve; Mehrabian, Margarete



Coating of open tubular capillaries with discoidal and spherical high-density lipoprotein particles in electrochromatography.  


A new method was developed for the coating of fused-silica capillaries with human high-density lipoproteins (HDLs) for use in electrochromatography. The HDL particles used for the coating differed in particle shape and composition. Both discoidal and spherical particles formed a monolayer on the inner silica wall as confirmed by atomic force microscopy. The effect of coating conditions, such as HDL concentration and coating time, was investigated with spherical HDL particles. Examination of the influence of pH on the coating stability also allowed the determination of pI values for the HDL particles attached to the capillary wall. The pI values for spherical and discoidal HDL particles were close to 5.0. The repeatabilities of the EOF mobility and the retention factors of the uncharged steroid hormones used as model compounds were exploited in the evaluation of the coating stability. The optimal coating was achieved with 0.1 mg/mL HDL protein and 50 min flushing with coating solution followed by 15 min standing time. Electrochromatography with HDL-coated open tubular capillaries offers a new tool for the study of HDL particle structure and transformations. PMID:17607811

Vainikka, Kati; Chen, Jie; Metso, Jari; Jauhiainen, Matti; Riekkola, Marja-Liisa



Chitosan-modified carbon nanotubes-based platform for low-density lipoprotein detection.  


We have fabricated an immunosensor based on carbon nanotubes and chitosan (CNT-CH) composite for detection of low density lipoprotein (LDL) molecules via electrochemical impedance technique. The CNT-CH composite deposited on indium tin oxide (ITO)-coated glass electrode has been used to covalently interact with anti-apolipoprotein B (antibody: AAB) via a co-entrapment method. The biofunctionalization of AAB on carboxylated CNT-CH surface has been confirmed by Fourier transform infrared spectroscopic and electron microscopic studies. The covalent functionalization of antibody on transducer surface reveals higher stability and reproducibility of the fabricated immunosensor. Electrochemical properties of the AAB/CNT-CH/ITO electrode have been investigated using cyclic voltammetric and impedimetric techniques. The impedimetric response of the AAB/CNT-CH/ITO immunoelectrode shows a high sensitivity of 0.953??/(mg/dL)/cm(2) in a detection range of 0-120 mg/dL and low detection limit of 12.5 mg/dL with a regression coefficient of 0.996. The observed low value of association constant (0.34 M(-1)s(-1)) indicates high affinity of AAB/CNT-CH/ITO immunoelectrode towards LDL molecules. This fabricated immunosensor allows quantitative estimation of LDL concentration with distinguishable variation in the impedance signal. PMID:25201210

Ali, Md Azahar; Singh, Nawab; Srivastava, Saurabh; Agrawal, Ved V; John, Renu; Onoda, M; Malhotra, Bansi D



Policosanol inhibits cholesterol biosynthesis and enhances low density lipoprotein processing in cultured human fibroblasts.  


Policosanol is a mixture of aliphatic primary alcohols isolated and purified from sugar cane wax, that induces cholesterol-lowering effects in experimental models and human beings. When human lung fibroblasts were incubated with policosanol for 48 hours prior to the experiment, a dose dependent inhibition of 14C-acetate incorporation into total cholesterol was observed, whereas labeled mevalonate incorporation was not inhibited. Even when cholesterol synthesis was not strongly inhibited, low density lipoprotein (LDL) processing was markedly enhanced. Thus, LDL binding, internalization and degradation were significantly increased after policosanol treatment. In addition, despite the fact that'cholesterol generation was not inhibited at the lowest dose of policosanol assayed, LDL processing was significantly increased. The current data indicate that policosanol inhibits cholesterol synthesis at the earliest steps of the cholesterol biosynthetic pathway. On the other hand, this study suggests that the increase in LDL processing may be partially explained by the inhibition of cholesterol biosynthesis, even though an sterol-independent mechanism might be responsible for the enhancement of LDL-receptor activity. PMID:8728831

Menendez, R; Fernandez, S I; Del Rio, A; Gonzalez, R M; Fraga, V; Amor, A M; Mas, R M



Radiation inactivation of binding sites for high density lipoproteins in human fibroblast membranes  

SciTech Connect

Radiation inactivation and target analysis were used to determine the molecular mass of the binding sites for high density lipoproteins (HDL) on membranes prepared from human fibroblasts. These membrane binding sites shared characteristics with the previously described HDL binding sites on whole fibroblasts in tissue culture. They exhibited the same affinity for HDL, the same ligand specificity, and the same sensitivity to proteolytic agents. They were also up-regulated by cholesterol loading of the cells. Kinetics of HDL dissociation from membrane binding sites could not be described by a single exponential function, indicating that HDL probably bind to multiple classes of sites on fibroblast membranes. After exposure to ionizing radiation, these sites decreased in number as an apparent single exponential function of radiation dose, corresponding to an average molecular mass of 16,000 +/- 1000 Da, which is smaller than any known cell-surface receptor protein. These data indicate that HDL binding sites on fibroblast membranes are not classical receptors in that they are kinetically heterogeneous and small in molecular mass.

Mendel, C.M.; Kunitake, S.T.; Kane, J.P.; Kempner, E.S.



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

NASA Astrophysics Data System (ADS)

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

Deitrick, Russell; Gibson, Emily; Razzaghi, Hamid



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


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

Nesan, Dinushan; Ng, Dominic S



Bile Acids Reduce Endocytosis of High-Density Lipoprotein (HDL) in HepG2 Cells  

PubMed Central

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

Rohrl, Clemens; Eigner, Karin; Fruhwurth, Stefanie; Stangl, Herbert



Antipsoriatic treatment extends beyond the skin: recovering of high-density lipoprotein function.  


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

Marsche, Gunther; Holzer, Michael; Wolf, Peter



Glucuronic Acid Epimerase Is Associated with Plasma Triglyceride and High Density Lipoprotein Cholesterol Levels in Turks  

PubMed Central

Summary We narrowed chromosome 15q21-23 linkage to plasma high density lipoprotein cholesterol (HDL-C) levels in atherogenic dyslipidemic Turkish families by fine mapping, then focused on glucuronic acid epimerase (GLCE), a heparan sulfate proteoglycan (HSPG) biosynthesis enzyme. HSPGs participate in lipid metabolism along with apolipoprotein (apo) E. Of 31 SNPs in the GLCE locus, nine analyzed by haplotype were associated with plasma HDL-C and triglyceride levels (permuted p = 0.006 and 0.013, respectively) in families. Of five tagging GLCE SNPs in two cohorts of unrelated subjects, three (rs16952868, rs11631403, rs3865014) were associated with triglyceride and HDL-C levels in males (non-permuted p < 0.05). The association was stronger in APOE 2/3 subjects (apoE2 has reduced binding to HSPGs) and reached multiple-testing significance (p < 0.05) in both males and females (n = 2612). Similar results were obtained in the second cohort (n = 1164). Interestingly, at the GLCE locus, bounded by recombination hotspots, Turks had a minor allele frequency of SNPs resembling Chinese more than European ancestry; adjoining regions on chromosome 15 resembled the European pattern. Studies of glce+/–apoe–/– mice fed a chow or high-fat diet supported a role for GLCE in lipid metabolism. Thus, SNPs in GLCE are associated with triglyceride and HDL-C levels in Turks, and mouse studies support a role for glce in lipid metabolism. PMID:21488854

Hodoglugil, Ugur; Williamson, David W.; Yu, Yi; Farrer, Lindsay A.; Mahley, Robert W.



Magnoflorine from Coptidis Rhizoma protects high density lipoprotein during oxidant stress.  


The objective of the present study was to investigate the beneficial properties of magnoflorine, an alkaloid isolated from coptidis rhizoma, on protecting human high density lipoprotein (HDL) against lipid peroxidation. Magnoflorine exerts an inhibitory effect against Cu2+-induced lipid peroxidation of HDL, as showed by prolongation of lag time from 62 to 123 min at the concentration of 3.0 microM. It also inhibits the generation of thiobarbituric acid reactive substances (TBARS) in the dose-dependent manners with IC50 values of 2.3+/-0.2 microM and 6.2+/-0.5 microM since HDL oxidation mediated by either catalytic Cu2+ or thermo-labile radical initiator (AAPH), respectively. Separately, Cu2+ oxidized HDL lost the antioxidant action but the inclusion of magnoflorine/Cu2+ oxidized HDL can protect LDL oxidation according to increasing magnoflorine concentration. The results suggest that magnoflorine may have a role to play in preventing the HDL oxidation. PMID:17541173

Hung, Tran Manh; Lee, Jong Pill; Min, Byung Sun; Choi, Jae Sue; Na, MinKyun; Zhang, XinFeng; Ngoc, Tran Minh; Lee, IkSoo; Bae, KiHwan



Aggregation and fusion of low-density lipoproteins in vivo and in vitro  

PubMed Central

Low-density lipoproteins (LDLs, also known as ‘bad cholesterol’) are the major carriers of circulating cholesterol and the main causative risk factor of atherosclerosis. Plasma LDLs are 20- to 25-nm nanoparticles containing a core of cholesterol esters surrounded by a phospholipid monolayer and a single copy of apolipoprotein B (550 kDa). An early sign of atherosclerosis is the accumulation of LDL-derived lipid droplets in the arterial wall. According to the widely accepted ‘response-to-retention hypothesis’, LDL binding to the extracellular matrix proteoglycans in the arterial intima induces hydrolytic and oxidative modifications that promote LDL aggregation and fusion. This enhances LDL uptake by the arterial macrophages and triggers a cascade of pathogenic responses that culminate in the development of atherosclerotic lesions. Hence, LDL aggregation, fusion, and lipid droplet formation are important early steps in atherogenesis. In vitro, a variety of enzymatic and nonenzymatic modifications of LDL can induce these reactions and thereby provide useful models for their detailed analysis. Here, we summarize current knowledge of the in vivo and in vitro modifications of LDLs leading to their aggregation, fusion, and lipid droplet formation; outline the techniques used to study these reactions; and propose a molecular mechanism that underlies these pro-atherogenic processes. Such knowledge is essential in identifying endogenous and exogenous factors that can promote or prevent LDL aggregation and fusion in vivo and to help establish new potential therapeutic targets to decelerate or even block these pathogenic reactions.

Gursky, Olga



Sphingomyelin in High-Density Lipoproteins: Structural Role and Biological Function  

PubMed Central

High-density lipoprotein (HDL) levels are an inverse risk factor for cardiovascular diseases, and sphingomyelin (SM) is the second most abundant phospholipid component and the major sphingolipid in HDL. Considering the marked presence of SM, the present review has focused on the current knowledge about this phospholipid by addressing its variable distribution among HDL lipoparticles, how they acquire this phospholipid, and the important role that SM plays in regulating their fluidity and cholesterol efflux from different cells. In addition, plasma enzymes involved in HDL metabolism such as lecithin–cholesterol acyltransferase or phospholipid transfer protein are inhibited by HDL SM content. Likewise, HDL SM levels are influenced by dietary maneuvers (source of protein or fat), drugs (statins or diuretics) and modified in diseases such as diabetes, renal failure or Niemann–Pick disease. Furthermore, increased levels of HDL SM have been shown to be an inverse risk factor for coronary heart disease. The complexity of SM species, described using new lipidomic methodologies, and their distribution in different HDL particles under many experimental conditions are promising avenues for further research in the future. PMID:23571495

Martinez-Beamonte, Roberto; Lou-Bonafonte, Jose M.; Martinez-Gracia, Maria V.; Osada, Jesus



Antibodies to oxidized low density lipoprotein: epidemiological studies and potential clinical applications in cardiovascular disease.  


The pathogenesis of atherosclerosis is mediated by genetic susceptibility along with a variety of cardiovascular risk factors and environment influences. As atherosclerotic lesions progress, they manifest several features typical of chronic inflammation, such as the presence of monocyte/macrophages, T-cells and inflammatory cytokines. This inflammatory response is fueled and enhanced by oxidative stress, which may be the link between lipid disorders and inflammation. Oxidation of lipoproteins is intimately involved in all stages of atherosclerosis and oxidative byproducts co-localize with inflammatory cells. When low density lipoprotein enters the subintimal space, it is oxidized by several mechanisms, including both enzymatic and non-enzymatic pathways and becomes a ligand for scavenger receptors on macrophages leading to generation of foam cells. Oxidized LDL is not only pro-inflammatory and pro-atherogenic, but several of the neoepitopes generated during oxidation are highly immunogenic and result in the generation of autoantibodies. Autoantibodies to OxLDL are found within atherosclerotic lesions and in apparently healthy subjects, as well as patients with various manifestations of cardiovascular disease. In this article, the role of circulating autoantibodies to OxLDL in cardiovascular disease will be reviewed. Although controversy still exists, the overall evidence supports the notion that IgG autoantibodies to OxLDL are associated with pro-atherogenic properties and IgM autoantibodies to OxLDL with atheroprotective properties. Whether such antibodies have a modulating role or are merely reflectors of atherogenesis has not been fully determined. Data is also emerging on the role of natural antibodies, which are primarily of the IgM class, that recognize oxidation-specific epitopes. Among other properties, these antibodies may be involved in housekeeping functions in binding and clearing pro-inflammatory oxidized lipids and therefore may be atheroprotective. Several studies have also recently evaluated the potential therapeutic role of antibodies to OxLDL either through active immunization using OxLDL or model oxidation-specific epitopes as immunogens or through passive immunization with human antibodies directed to oxidation-specific epitopes. Although these investigation are at an early stage, they show promise that immune modulation may lead to novel approaches to treat atherosclerosis and cardiovascular disease. PMID:18091649

Gounopoulos, P; Merki, E; Hansen, L F; Choi, S-H; Tsimikas, S




Microsoft Academic Search

We examined the expression of macrophage migration inhibitory factor (MIF) mRNA in murine macrophage cell line (RAW 264.7 cells) in response to oxidized low-density lipoprotein (oxLDL), and investigated the influence of MIF on the uptake and degradation of oxLDL by RAW 264.7 cells. MIF mRNA expression was markedly upregulated in the presence of oxLDL. Consistent with this, the MIF level

Toshiya Atsumi; Jun Nishihira; Zenji Makita; Takao Koike



Effect of lipid transfer activity and triglyceride hydrolysis on apolipoprotein B immunoreactivity in modified low density lipoproteins  

Microsoft Academic Search

Consequences of alterations in the size and the lipid composition of low density lipoproteins (LDL) on apoli- poprotein (apo) B immunoreactivity were analyzed using two distinct anti-apoB monoclonal antibodies (Mabs), Le., 4G3, which recognizes an epitope closed to the binding site to the LDL receptor, and 2D8, which is directed against a distal re- gion. Inhibition analysis revealed that the

Laurent Lagrost


Autoxidation of human low density lipoprotein: loss of polyunsaturated fatty acids and vitamin E and generation of aldehydes  

Microsoft Academic Search

The alteration of structural and biological properties of human plasma low density lipoprotein (LDL) exposed to ox- idative conditions is in part ascribed to lipid peroxidation. The objective of this investigation was to measure quantitatively several parameters in oxidizing LDL indicative for lipid perox- idation. Exposure of freshly prepared ElYLA-free LDL to an oxygen-saturated buffer led to a complete depletion

Hermann Esterbauer; Gunther Jurgens; Oswald Quehenberger; Ernst Koller


Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers  

Microsoft Academic Search

The aim of our study was to evaluate the effect of a standardized formulation of a polyphenolic extract of grapes (Leucoselect-Phytosome [LP]) on low-density lipoprotein (LDL) susceptibility to oxidation in a group of heavy smokers. A randomized, double-blind, crossover study was undertaken in 24 healthy male heavy smokers, aged ? 50 years. Enrolled subjects were given 2 capsules twice daily

Giovanni B Vigna; Fabrizio Costantini; Giancarlo Aldini; Marina Carini; Alberico Catapano; Fabio Schena; Arianna Tangerini; Rosanna Zanca; Egidio Bombardelli; Paolo Morazzoni; Andrea Mezzetti; Renato Fellin; Roberto Maffei Facino



Ginkgo Biloba Extract (EGb 761) Protects Human Low-Density Lipoproteins against Oxidative Modification Mediated by Copper  

Microsoft Academic Search

The antioxidant effects of Ginkgo biloba extract (EGb 761) on copper-mediated human low density lipoprotein (LDL) oxidative modification were evaluated by several techniques. Human LDL (0.5 mg\\/ml) in phosphate buffered saline, pH 7.4, was incubated with 10 ?M cupric sulfate at 37°C under air for 8 hours and 24 hours in the presence of varying concentrations of EGb 761. Increases

L. J. Yan; M. T. Droylefaix; L. Packer



Adenovirus-Mediated Transfer of Low Density Lipoprotein Receptor Gene Acutely Accelerates Cholesterol Clearance in Normal Mice  

Microsoft Academic Search

We have explored the use of adenovirus-mediated gene transfer to transiently elicit production of low density lipoprotein (LDL) receptors in mice. A recombinant adenovirus carrying the human LDL receptor cDNA restored LDL receptor function in receptor-deficient cultured cells. Intravenous injection of recombinant virus acutely lowered plasma cholesterol levels and increased the rate of 125I-labeled LDL clearance from the circulation in

Joachim Herz; Robert D. Gerard



Effects of low doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol levels in patients with hypercholesterolemia  

Microsoft Academic Search

Background: Simvastatin 40 to 80 mg\\/d has been found to increase high-density lipoprotein cholesterol (HDL-C) levels significantly more than atorvastatin at equipotent doses (ie, 20–80 mg\\/d). Data on the effects of lower doses of the 2 drugs on HDL-C levels are conflicting.Objective: The purpose of this study was to investigate the effects of simvastatin 20 mg\\/d and atorvastatin 10 mg\\/d

Adriana Branchi; Anna M. Fiorenza; Adriana Torri; Fulvio Muzio; Cristina Berra; Emanuela Colombo; Elena Dalla Valle; Angelo Rovellini; Domenico Sommariva



High-density lipoprotein cholesterol and triglycerides as therapeutic targets for preventing and treating coronary artery disease  

Microsoft Academic Search

Epidemiologic and clinical trials show that elevated triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C) are independent risk factors for coronary heart disease (CHD). However, adjustment for covariates frequently weakens or abolishes the predictive significance of triglycerides, whereas the evidence for HDL-C is more consistently strong. Data indicate that there is a 2% to 3% decrease in coronary risk

Antonio M. Gotto



Additive effect of plant sterol-ester margarine and cerivastatin in lowering low-density lipoprotein cholesterol in primary hypercholesterolemia  

Microsoft Academic Search

The objective of this study was to evaluate whether plant sterol-ester margarine has an additive or interactive effect on low-density lipoprotein (LDL) cholesterol reduction when ingested in combination with a statin drug. This was a multicenter, randomized, double-blind study with 4 parallel treatment arms in a balanced 2 × 2 factorial design. The 4 daily treatment options were: (1) placebo

Leon A Simons



Members of the Low Density Lipoprotein Receptor Family Mediate Cell Entry of a Minor-Group Common Cold Virus  

Microsoft Academic Search

A protein binding to a minor-group human rhinovirus (HRV2) was purified from HeLa cell culture supernatant. The amino acid sequences of tryptic peptides showed identity with the human low density lipoprotein (LDL) receptor (LDLR). LDL and HRV2 mutually competed for binding sites on human fibroblasts. Cells down-regulated for LDLR expression yielded much less HRV2 upon infection than cells with up-regulated

Franz Hofer; Martin Gruenberger; Heinrich Kowalski; Herwig Machat; Manfred Huettinger; Ernst Kuechler; Dieter Blaas



Elevated Levels of Oxidized Low Density Lipoprotein Show a Positive Relationship With the Severity of Acute Coronary Syndromes  

Microsoft Academic Search

Background—There is accumulating data that acute coronary syndromes relate to recent onset activation of inflammation affecting atherosclerotic plaques. Increased blood levels of oxidized low density lipoprotein (ox-LDL) could play a role in these circumstances. Methods and Results—Ox-LDL levels were measured in 135 patients with acute myocardial infarction (AMI; n 545), unstable angina pectoris (UAP; n545), and stable angina pectoris (SAP;

Shoichi Ehara; Makiko Ueda; Takahiko Naruko; Kazuo Haze; Akira Itoh; Masato Otsuka; Ryushi Komatsu; Toshihiko Matsuo; Hiroyuki Itabe; Tatsuya Takano; Yoshiaki Tsukamoto; Minoru Yoshiyama; Kazuhide Takeuchi; Junichi Yoshikawa; Anton E. Becker



Complete Deficiency of the Low-Density Lipoprotein Receptor Is Associated With Increased Apolipoprotein B100 Production  

Microsoft Academic Search

Objective—We addressed the role of the low-density lipoprotein (LDL) receptor in determining clearance rates and production rate (PR) of apolipoprotein B (apoB) in humans. Methods and Results—Kinetic studies using endogenous labeling of apoB with deuterated leucine were performed in 7 genetically defined patients with homozygous familial hypercholesterolemia (FH) and compared with 4 controls. The fractional catabolic rates (FCR) and PRs

John S. Millar; Cyrille Maugeais; Katsunori Ikewaki; Daniel M. Kolansky; P. Hugh; R. Barrett; Elaine C. Budreck; Raymond C. Boston; Norio Tada; Seibu Mochizuki; Joep C. Defesche; James M. Wilson; Daniel J. Rader



Localization of the gene for high-density lipoprotein binding protein (HDLBP) to human chromosome 2q37  

SciTech Connect

The high-density lipoprotein binding protein (HDLbp) is a 110-kDa protein that specifically binds HDL molecules and may function in the removal of excess cellular cholesterol. As part of an effort to study the function of the protein and its possible role in cholesterol transport, the authors report the localization of the gene for HDLbp, designated HDLBP, to human chromosome 2q37 using analysis of somatic cell hybrids and in situ hybridization. 14 refs., 1 fig.

Xia, Y.R.; Klisak, I.; Sparkes, R.S.; Lusis, A.J. [Univ. of California, Los Angeles, CA (United States)] [Univ. of California, Los Angeles, CA (United States); Oram, J. [Univ. of Washington, Seattle, WA (United States)] [Univ. of Washington, Seattle, WA (United States)



Factors associated with low and elevated plasma high density lipoprotein cholesterol and apolipoprotein AI levels in the Framingham Offspring Study  

Microsoft Academic Search

A decreased high density lipoprotein (HDL) cholesterol level ( < 35 mg\\/dl) has been shown to be a significant independent risk factor for coronary heart disease (CHD). Moreover, increased HDL cholesterol levels (260 mg\\/dl) are as- sociated with a decreased CHD risk. Levels of HDL cholesterol and apoA-I, the major protein constituent of HDL, were mea- sured in plasma from

Ernst J. Schaefer; Stefania Lamon-Fava; Jose M. Ordovas; L Susan; D. Cohn; Mary M. Schaefer; William P. Castelli; Peter W. F. Wilsont


Consumption of Saturated Fat Impairs the Anti-Inflammatory Properties of High-Density Lipoproteins and Endothelial Function  

Microsoft Academic Search

OBJECTIVES The purpose of this study was to investigate the influence of dietary fatty acids on the anti-inflammatory properties of high-density lipoproteins (HDL) and vascular function. BACKGROUND The effect of dietary fatty acids on atherogenesis remains uncertain. METHODS Fourteen adults consumed an isocaloric meal containing either a polyunsaturated or a saturated fat on 2 occasions. The effects of post-prandial HDL

Stephen J. Nicholls; Pia Lundman; Jason A. Harmer; Belinda Cutri; Kaye A. Griffiths; Kerry-Anne Rye; Philip J. Barter; David S. Celermajer



Low-density lipoprotein particle size in hepatic steatosis and metabolic syndrome  

PubMed Central

Background Hepatic steatosis (HS), the most frequent liver disorder, was reported to be an independent predictor of cardiovascular disease. HS, if combined with the metabolic syndrome (MetS), might have a synergistic effect on low-density lipoprotein (LDL) particle size. Methods Carotid intima-media thickness (IMT) and plaque formation, and HS were diagnosed ultrasonographically, and the MetS was diagnosed using the ATP III criteria in 274 healthy workers (mean age ± SD, 43.5 ± 7.1 yrs). LDL particle size was measured with density gradient ultracentrifugation, and subfractions were classified as large, buoyant LDL I (27.2~28.5 nm) and small, dense LDL III (24.2~25.5). All participants were grouped into three categories: control, subjects with HS alone and those with both HS and the MetS. Results The subjects with HS alone were 84 (30.7%), whereas those with HS and the MetS were 46 (16.8%). LDL peak particle sizes showed significant negative correlations with carotid mean IMTs. LDL peak particle size and LDL I (%) decreased significantly in the HS, showing the lowest values in the subjects with both HS and the MetS, and their association was independent, even adjusted for potential confounders. LDL III also showed independent associations across the groups. Conclusion HS alone was more prevalent than HS combined with the MetS in general population. For the patients with HS alone, LDL particle size and carotid atherosclerosis were found to fall in the middle of the control and those with both HS and the MetS. PMID:20307304



Retroendocytosis of high density lipoproteins by the human hepatoma cell line, HepG2  

SciTech Connect

When human HepG2 hepatoma cells were pulsed with 125I-labeled high density lipoproteins (HDL) and chased in fresh medium, up to 65% of the radioactivity released was precipitable with trichloroacetic acid. Cell-internalized 125I-HDL contributed to the release of acid-precipitable material; when cells were treated with trypsin before the chase to remove 125I-HDL bound to the outer cell membrane, 50% of the released material was still acid-precipitable. Characterization of the radioactive material resecreted by trypsinized cells revealed the presence of particles that were similar in size and density to mature HDL and contained intact apolipoproteins (apo) A-I and A-II. The release of internalized label occurred at 37 degrees C but not at 4 degrees C. Monensin, which inhibits endosomal recycling of receptors, decreased the binding of 125I-HDL to cells by 75%, inhibited the release of internalized radioactivity as acid-precipitable material by 80%, and increased the release of acid-soluble material by 90%. In contrast, the lysosomal inhibitor chloroquine increased the association of 125I-HDL to cells by 25%, inhibited the release of precipitable material by 10%, and inhibited the release of acid-soluble radioactivity by 80%. Pre-incubation with cholesterol caused a 50% increase in the specific binding, internalization, and resecretion of HDL label. Cholesterol affected the release of acid-precipitable label much more (+90%) than that of acid-soluble material (+20%). Taken together, these findings suggest that HepG2 cells can bind, internalize, and resecrete HDL by a retroendocytotic process. Furthermore, the results with cholesterol and monensin indicate that a regulated, recycling, receptor-like molecule is involved in the binding and intracellular routing of HDL.

Kambouris, A.M.; Roach, P.D.; Calvert, G.D.; Nestel, P.J. (CSIRO, Division of Human Nutrition, Adelaide (Australia))



Oxidation of serum low-density lipoprotein (LDL) and antioxidant status in young and elderly humans  

Microsoft Academic Search

The incidence of atherosclerosis increases with age, as do various indices of free-radical mediated damage, e.g., lipid peroxidation. Because lipid peroxidation plays a prominent role in lipoprotein oxidation, likely a prelude to atherosclerosis, we compared the susceptibility of lipoproteins to oxidation in young (19–30 years) and elderly (59–86 years) groups. Although we found no significant differences in serum malondialdehyde (MDA)

Yukiko K. Nakamura; Marsha H. Read; Jeffrey W. Elias



Serum amyloid A stimulates macrophage foam cell formation via lectin-like oxidized low-density lipoprotein receptor 1 upregulation  

SciTech Connect

Highlights: ? SAA induced macrophage foam cell formation. ? SAA stimulated upregulation of lectin-like oxidized low-density lipoprotein receptor 1 (LOX1). ? SAA-induced LOX1 expression and foam cell formation is mediated by JNK/NF-?B signaling. ? HDL-conjugated SAA also stimulates foam cell formation via LOX1 upregulation. ? The finding reveals a novel mechanism of action of SAA in the pathogenesis of atherosclerosis. -- Abstract: Elevated levels of serum amyloid A (SAA) is a risk factor for cardiovascular diseases, however, the role of SAA in the pathophysiology of atherosclerosis remains unclear. Here we show that SAA induced macrophage foam cell formation. SAA-stimulated foam cell formation was mediated by c-jun N-terminal kinase (JNK) signaling. Moreover, both SAA and SAA-conjugated high density lipoprotein stimulated the expression of the important scavenger receptor lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) via nuclear factor-?B (NF-?B). A LOX1 antagonist carrageenan significantly blocked SAA-induced foam cell formation, indicating that SAA promotes foam cell formation via LOX1 expression. Our findings therefore suggest that SAA stimulates foam cell formation via LOX1 induction, and thus likely contributes to atherogenesis.

Lee, Ha Young, E-mail: [Department of Biological Science, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Kim, Sang Doo [Department of Biological Science, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of)] [Department of Biological Science, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Baek, Suk-Hwan [Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of)] [Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Choi, Joon Hyuk [Department of Pathology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of)] [Department of Pathology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Cho, Kyung-Hyun [School of Biotechnology, Yeungnam University, Gyeongsan 712-749 (Korea, Republic of)] [School of Biotechnology, Yeungnam University, Gyeongsan 712-749 (Korea, Republic of); Zabel, Brian A. [Palo Alto Institute for Research and Education, Veterans Affairs Hospital, Palo Alto, CA 94304 (United States)] [Palo Alto Institute for Research and Education, Veterans Affairs Hospital, Palo Alto, CA 94304 (United States); Bae, Yoe-Sik, E-mail: [Department of Biological Science, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of) [Department of Biological Science, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714 (Korea, Republic of); Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 135-710 (Korea, Republic of)



Tissue specific regulation of the high density lipoprotein (HDL) receptor, scavenger receptor Class B, Type I (SR-BI) by the scaffold protein PDZK1  

E-print Network

PDZK1 is a four PDZ-domain containing cytoplasmic adaptor protein that binds the Cterminus of the high-density lipoprotein (HDL) receptor SR-BI. Abolishing PDZK1 expression in PDZK1 knockout (KO) mice leads to a ...

Fenske, Sara Anne



Nascent very-low-density lipoprotein triacylglycerol hydrolysis by lipoprotein lipase is inhibited by apolipoprotein E in a dose-dependent manner.  

PubMed Central

In the present study it was investigated whether apolipoprotein (apoE) can inhibit the lipoprotein lipase (LPL)-mediated hydrolysis of very-low-density-lipoprotein (VLDL) triacylglycerols (TAGs). Previous studies have suggested such an inhibitory role for apoE by using as a substrate for LPL either plasma VLDL or artificial TAG emulsions. To mimic the in vivo situation more fully, we decided to investigate the effect of apoE on the LPL-mediated TAG hydrolysis by using VLDL from apoE-deficient mice that had been enriched with increasing amounts of apoE. Furthermore, since plasma VLDL isolated from apoE-deficient mice was relatively poor in TAGs and strongly enriched in cholesterol as compared with VLDL from wild-type mice, we used nascent VLDL obtained by liver perfusions. Nascent VLDL (d<1. 006) isolated from the perfusate of the apoE-deficient mouse liver was rich in TAGs. Addition of increasing amounts of apoE to apoE-deficient nascent VLDL effectively decreased TAG lipolysis as compared with that of apoE-deficient nascent VLDL without the addition of apoE (63.1+/-6.3 and 20.8+/-1.8% of the control value at 2.7 microg and 29.6 microg of apoE/mg of TAG added respectively). Since, in vivo, LPL is attached to heparan sulphate proteoglycans (HSPG) at the endothelial matrix, we also performed lipolysis assays with LPL bound to HSPG in order to preserve the interaction of the lipoprotein particle with the HSPG-LPL complex. In this lipolysis system a concentration-dependent decrease in the TAG lipolysis was also observed with increasing amounts of apoE on nascent VLDL, although to a lesser extent than with LPL in solution (72.3+/-3.6% and 56.6+/-1.7% of control value at 2.7 microg and 29.6 microg of apoE/mg TAGs added respectively). In conclusion, the enrichment of the VLDL particle with apoE decreases its suitability as a substrate for LPL in a dose-dependent manner. PMID:9396715

Jong, M C; Dahlmans, V E; Hofker, M H; Havekes, L M



Knowledge-Driven Analysis Identifies a Gene–Gene Interaction Affecting High-Density Lipoprotein Cholesterol Levels in MultiEthnic Populations  

Microsoft Academic Search

Total cholesterol, low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease. We tested for gene–gene interactions affecting the level of these four lipids based on prior knowledge of established genome-wide association study (GWAS) hits, protein–protein interactions, and pathway information. Using genotype data from 9,713 European Americans from the

Li Ma; Ariel Brautbar; Eric Boerwinkle; Charles F. Sing; Andrew G. Clark; Alon Keinan



Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events  

Microsoft Academic Search

The relationship between autoantibodies to oxi- dized low density lipoprotein (OxLDL) and coronary artery disease (CAD) remains controversial. IgM and IgG OxLDL autoantibodies to malondialdehyde (MDA)-modified LDL, copper oxidized low density lipoprotein (CuOxLDL), and oxidized cholesterol linoleate (OxCL), as well as apolipo- protein B-100 immune complexes (apoB-ICs), were mea- sured in 504 patients undergoing clinically indicated coronary angiography. Patients were

Sotirios Tsimikas; Emmanouil S. Brilakis; Ryan J. Lennon; Elizabeth R. Miller; Joseph L. Witztum; Joseph P. McConnell; Kenneth S. Kornman; Peter B. Berger



Hepatic metabolism of colloidal gold-low-density lipoprotein complexes in the rat: evidence for bulk excretion of lysosomal contents into bile  

Microsoft Academic Search

Rats were treated with 17 alpha-ethinyl estradiol to induce high levels of low-density lipoprotein receptors in hepatocytes. When these rats were given intravenous injections of low-density lipoprotein-colloidal gold complexes, most of the gold (labeled with ¹⁹⁵Au) appeared to be taken up by Kupffer cells, as were complexes of colloidal gold with albumin or polyvinylpyrrolidone. However, when these rats were also

Guy Renaud; Robert L. Hamilton; Richard J. Havel



Metabolic basis of high density lipoproteins and apolipoprotein AI increase by HMG-CoA reductase inhibition in healthy subjects and a patient with coronary artery disease  

Microsoft Academic Search

HMG-CoA reductase inhibitors, such as pravastatin, are widely used as lipid lowering drugs in hypercholesterolemia. Pravastatin does not only reduce the atherogenic low density lipoprotein (LDL)-cholesterol, but is also increasing high density lipoprotein (HDL)-cholesterol. However, the mechanism leading to an increase of HDL are unclear. Therefore, the effects of pravastatin on the in vivo kinetics of apolipoprotein (apo) A-I were

J. R. Schaefer; H. Schweer; K. Ikewaki; H. Stracke; H. J. Seyberth; H. Kaffarnik; B. Maisch; A. Steinmetz



Insulin-like growth factor I and low-density-lipoprotein cholesterol in women during high- and low-fat feeding13  

Microsoft Academic Search

In vitro studies suggest that insulin-like growth factor I (IGF-I) may modulate hepatic production and peripheral utilization of lipoproteins. We measured blood concentrations of IGF-I; total, high-density-lipoprotein, and low-density-lipo- protein (LDL) cholesterol; and apolipoproteins in 18 women with above average cholesterol after high- and low-fat diet pe- nods. Total cholesterol fell 6% (P < 0.02) during the low-fat diet because

T Elaine Prewilt; Terry G Unterman; Roberta Glick; Thomas G Cole; Dale Schmeisser; Phyllis E Bowen; Patricia Langenberg


Effects of age, gender, and menopausal status on plasma low density lipoprotein cholesterol and apolipoprotein B levels in the Framingham Offspring Study  

Microsoft Academic Search

Plasma low density lipoprotein (LDL) cholesterol, non-high density lipoprotein (HDL) cholesterol, and apolipoprotein (apo) B, the major protein constituent of LDL, were measured in 1,533 men (mean age 49 f 10 years) and 1,597 women (mean age 49 f 10 years) participating in the 3rd exami- nation cycle of the Framingham Offspring Study. Mean plasma levels of LDL cholesterol and

Ernst J. Schaefer; Stefania Lamon-Fava; Susan D. Cohn; Mary M. Schaefer; Jose M. Ordovas; William P. Castelli; Peter W. F. Wilson


Transcriptional Activation of Low Density Lipoprotein Receptor Gene by Angiotensin-Converting Enzyme Inhibitors and Ca2+Channel Blockers Involves Protein Kinase C Isoforms  

Microsoft Academic Search

The pharmacological potency of angiotensin-converting enzyme (ACE) inhibitors (lisinopril and enalaprilat) on the transcription of low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase genes was examined in human vascular smooth muscle cells and compared with the action of Ca2+-channel blockers (manidipine, verapamil, and diltiazem). Analogous to Ca2+-channel blockers, nanomolar concentrations of enalaprilat or lisinopril stimulated the synthesis of low density lipoprotein

Lutz H. Block; Radovan Keul; Maryse Crabos; Rolf Ziesche; Michael Roth



Low density lipoprotein receptor gene Ava II polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations  

Microsoft Academic Search

Background  Several common genetic polymorphisms in the low density lipoprotein receptor (LDL-R) gene have associated with modifications\\u000a of serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels, but the results are not consistent\\u000a in different populations. Bai Ku Yao is a special subgroup of the Yao minority in China. The present study was undertaken\\u000a to detect the association of

Xing-Jiang Long; Rui-Xing Yin; Ke-La Li; Wan-Ying Liu; Lin Zhang; Xiao-Li Cao; Lin Miao; Dong-Feng Wu; Lynn Htet Htet Aung; Xi-Jiang Hu



Bovine aortic endothelial cells express a variant of the very low density lipoprotein receptor that lacks the O-linked sugar domain 1  

Microsoft Academic Search

The very low density lipoprotein (VLDL) recep- tor is a member of the low density lipoprotein supergene family of receptors in which differential splicing of mRNA has been reported. We present several lines of evidence showing that bovine aortic endothelial cells exclusively ex- press a VLDL receptor isoform that lacks the O-linked sugar domain i ) Western and receptor-associated protein

Jordi Magrané; Manuel Reina; Roser Pagan; Ana Luna; Ricardo P. Casaroli-Marano; Bo Angelin; Mats Gåfvels; Senén Vilaró


Low-density lipoproteins are degraded in HepG2 cells with low efficiency.  

PubMed Central

In previous studies we have shown that in HepG2 cells, as compared with fibroblasts, the low-density lipoprotein (LDL) receptor is only weakly down-regulated upon incubation of the cells with LDL. To explain this difference in down-regulation of the LDL-receptor activity, we studied simultaneously the intracellular processing of 125I-labelled LDL in both cell lines. Upon incubation of HepG2 cells with 125I-LDL, the appearance of degradation products started at 90 min, whereas in fibroblasts this lag time was only 30 min. The degradation efficiency (representing the ratio degradation/cell association of LDL) in HepG2 was less than 50% of that in fibroblasts up to 5h of incubation at 37 degrees C. The longer lag time and low efficiency of the degradation of LDL in HepG2 cells were independent of the cell density. Pulse-chase experiments indicated that the internalization rate of surface-bound LDL in HepG2 cells is similar to that of fibroblasts. Endosomal loading of 125I-LDL by incubation at 18 degrees C for 4.5 h, followed by a shift to 37 degrees C, resulted in degradation of LDL within 30 min in fibroblasts, whereas in HepG2 cells the lag time of the degradation was 90 min. In parallel experiments using subcellular fractionation by Percoll-gradient centrifugation of homogenized cells and 125I-tyramine-cellobiose-labelled LDL, we observed that in both cell types LDL is equally rapidly shifted from a low- to a high-density compartment (within 15 min), representing the endosomal and the late-endosomal plus lysosomal compartment respectively. We conclude that in HepG2 cells the cell-bound LDL, upon internalization, goes through the intracellular itinerary at the same rate as in fibroblasts, but that either the fusion between late endosomes and lysosomes or the lysosomal degradation itself is proceeding at a lower efficiency. A low degradation rate of LDL may contribute to explain the relatively weak down-regulation of the LDL-receptor activity in HepG2 cells by LDL. PMID:8452540

Lombardi, P; Mulder, M; de Wit, E; van Berkel, T J; Frants, R R; Havekes, L M



The Oxidized Low-Density Lipoprotein Receptor Mediates Vascular Effects of Inhaled Vehicle Emissions  

PubMed Central

Rationale: To determine vascular signaling pathways involved in inhaled air pollution (vehicular engine emission) exposure–induced exacerbation of atherosclerosis that are associated with onset of clinical cardiovascular events. Objectives: To elucidate the role of oxidized low-density lipoprotein (oxLDL) and its primary receptor on endothelial cells, the lectin-like oxLDL receptor (LOX-1), in regulation of endothelin-1 expression and matrix metalloproteinase activity associated with inhalational exposure to vehicular engine emissions. Methods: Atherosclerotic apolipoprotein E knockout mice were exposed by inhalation to filtered air or mixed whole engine emissions (250 ?g particulate matter [PM]/m3 diesel + 50 ?g PM/m3 gasoline exhausts) 6 h/d for 7 days. Concurrently, mice were treated with either mouse IgG or neutralizing antibodies to LOX-1 every other day. Vascular and plasma markers of oxidative stress and expression proatherogenic factors were assessed. In a parallel study, healthy human subjects were exposed to either 100 ?g PM/m3 diesel whole exhaust or high-efficiency particulate air and charcoal-filtered “clean” air (control subjects) for 2 hours, on separate occasions. Measurements and Main Results: Mixed emissions exposure increased oxLDL and vascular reactive oxygen species, as well as LOX-1, matrix metalloproteinase-9, and endothelin-1 mRNA expression and also monocyte/macrophage infiltration, each of which was attenuated with LOX-1 antibody treatment. In a parallel study, diesel exhaust exposure in volunteer human subjects induced significant increases in plasma-soluble LOX-1. Conclusions: These findings demonstrate that acute exposure to vehicular source pollutants results in up-regulation of vascular factors associated with progression of atherosclerosis, endothelin-1, and matrix metalloproteinase-9, mediated through oxLDL–LOX-1 receptor signaling, which may serve as a novel target for future therapy. PMID:21493736

Lucero, JoAnn; Harman, Melissa; Madden, Michael C.; McDonald, Jacob D.; Seagrave, Jean Clare; Campen, Matthew J.



Assessment of the Validity of the Double Superhelix Model for Reconstituted High Density Lipoproteins  

PubMed Central

For several decades, the standard model for high density lipoprotein (HDL) particles reconstituted from apolipoprotein A-I (apoA-I) and phospholipid (apoA-I/HDL) has been a discoidal particle ?100 ? in diameter and the thickness of a phospholipid bilayer. Recently, Wu et al. (Wu, Z., Gogonea, V., Lee, X., Wagner, M. A., Li, X. M., Huang, Y., Undurti, A., May, R. P., Haertlein, M., Moulin, M., Gutsche, I., Zaccai, G., Didonato, J. A., and Hazen, S. L. (2009) J. Biol. Chem. 284, 36605–36619) used small angle neutron scattering to develop a new model they termed double superhelix (DSH) apoA-I that is dramatically different from the standard model. Their model possesses an open helical shape that wraps around a prolate ellipsoidal type I hexagonal lyotropic liquid crystalline phase. Here, we used three independent approaches, molecular dynamics, EM tomography, and fluorescence resonance energy transfer spectroscopy (FRET) to assess the validity of the DSH model. (i) By using molecular dynamics, two different approaches, all-atom simulated annealing and coarse-grained simulation, show that initial ellipsoidal DSH particles rapidly collapse to discoidal bilayer structures. These results suggest that, compatible with current knowledge of lipid phase diagrams, apoA-I cannot stabilize hexagonal I phase particles of phospholipid. (ii) By using EM, two different approaches, negative stain and cryo-EM tomography, show that reconstituted apoA-I/HDL particles are discoidal in shape. (iii) By using FRET, reconstituted apoA-I/HDL particles show a 28–34-? intermolecular separation between terminal domain residues 40 and 240, a distance that is incompatible with the dimensions of the DSH model. Therefore, we suggest that, although novel, the DSH model is energetically unfavorable and not likely to be correct. Rather, we conclude that all evidence supports the likelihood that reconstituted apoA-I/HDL particles, in general, are discoidal in shape. PMID:20974855

Jones, Martin K.; Zhang, Lei; Catte, Andrea; Li, Ling; Oda, Michael N.; Ren, Gang; Segrest, Jere P.



Adrenal imaging with technetium-99m-labelled low density lipoproteins  

SciTech Connect

Plasma low density lipoproteins (LDL) are a major source of cholesterol for adrenal cortical steroid hormones synthesis. To test whether LDL labelled with Tc-99m could be used to assess adrenal cortical function, the authors prepared Tc-99m-LDL by dithionite reduction of Tc0/sub 4//sup -/ in the presence of LDL. About 80% of the Tc-LDL bonds were covalent. Purified Tc-99m-LDL was injected intravenously into 16 rabbits (4 t 8mCi/rabbit). External imaging was carried out 16 to 18 hrs later, at which time the adrenals were visualized clearly; the animals were sacrificed, the organs dissected out, weighed, and counted. The biodistribution demonstrated that 0.8l +- 0.19% of the injected radioactivity was taken up per gm of whole adrenal gland. This compared with an uptake of 0.19 +- 0.02% per gm by liver, 0.22 +- 0.04% per gm by spleen, and 0.11 +- 0.02% per gm by kidney. To verify that they were indeed imaging the adrenals, additional rabbits were tested with dexamethasone. First they were injected with Tc-99m-LDL; 28 hrs later the adrenals were again well visualized. Then the rabbits were given dexamethasone for 5 days to suppress adrenal cortical function. The adequacy of suppression was monitored by serum cortisol measurements. When Tc-99m-LDL was injected again, the adrenals could not be seen 18 hrs later. Counts of the adrenals from the suppressed rabbits were at background levels. These data indicate that Tc-99m-LDL is a useful radiopharmaceutical for evaluating adrenal cortical function.

Isaacsohn, J.L.; Lees, A.M.; Lees, R.S.; Kovach, M.B.; Strauss, H.W.



Italian Multicenter Study on Low-Density Lipoprotein Apheresis: retrospective analysis (2007).  


A retrospective study--the Italian Multicenter Study on Low-density Lipoprotein Apheresis (IMS-LDLa)--was carried out, which involved 19 centers for LDLa in Italy, distributed all over the country--in the north, center, south, and the major islands. The survey was conducted through two consecutive questionnaires, which can be downloaded online from a dedicated site. The total number of procedures performed until 2007 was 31 012, and the number of patients undergoing treatment until 2007 were 229. The treated patients still surviving consisted of 136 (74 males and 62 females); those surviving but not treated numbered 95, and those deceased numbered 14. The techniques utilized, listed by frequency of use, were the following: dextran sulfate cellulose adsorption, direct adsorption of lipids (DALI), heparin extracorporeal LDL precipitation, immunoadsorption, plasma-exchange, cascade filtration, and Lipocollect 200. The mean treated plasma and blood volumes per session were 3916.5 mL and 8735.1 mL, respectively. The most frequently utilized vascular access points were: venous 84.4% and arteriovenous fistula 15.5%. Hematoma by venipuncture (230 episodes), low outlet flow (125 episodes), and circuit coagulation (44 episodes) were reported as to be the most frequent side effects. In the second questionnaire (filled in by 19 centers) the centers were asked to report their data on: quality diagnosis of dyslipidemia and referents for genetic-molecular and clinical diagnosis, cholesterol-lowering drugs and dosages, typology of cardiovascular check-ups at the beginning of treatment and in follow-up, non-cholesterol-lowering drugs with priority for cardiologic drugs, including oral anti-coagulants, and, lastly, information related to the appropriateness of curing patients still under treatment with LDLa and, where possible, news on patients no longer under treatment. PMID:20438522

Stefanutti, Claudia



Cryoprotective effects of low-density lipoproteins, trehalose and soybean lecithin on murine spermatogonial stem cells.  


Summary Spermatogonial stem cells (SSCs) have the ability to self-renew and offer a pathway for genetic engineering of the male germ line. Cryopreservation of SSCs has potential value for the treatment of male infertility, spermatogonial transplantation, and so on. In order to investigate the cryopreservation effects of different cryoprotectants on murine SSCs, 0.2 M of low-density lipoproteins (LDL), trehalose and soybean lecithin were added to the cryoprotective medium, respectively, and the murine SSCs were frozen at -80°C or -196°C. The results indicated that the optimal recovery rates of murine SSCs in the cryoprotective medium supplemented with LDL, trehalose and soybean lecithin were 92.53, 76.35 and 75.48% at -80°C, respectively. Compared with freezing at -196°C, the optimum temperature for improvement of recovery rates of frozen murine SSCs, cryopreservation in three different cryoprotectants at -80°C, were 17.11, 6.68 and 10.44% respectively. The recovery rates of murine SSCs in the cryoprotective medium supplemented with 0.2 M LDL were significantly higher than that of other cryoprotectants (P < 0.05). Moreover, the recovery rates were demonstrated to be greater at -80°C compared with at -196°C (P < 0.05). In conclusion, 0.2 M of LDL could significantly protect murine SSCs at -80°C. In the freezing-thawing process, LDL is responsible for the cryopreservation of murine SSCs because it can form a protective film at the surface of membranes. However, more research is needed to evaluate and understand the precise role of LDL during the freezing-thawing of SSCs. PMID:22974447

Wang, Peng; Li, Ying; Hu, Xiao-Chen; Cai, Xiao-Li; Hou, Li-Peng; Wang, Yan-Feng; Hu, Jian-Hong; Li, Qing-Wang; Suo, Li-Juan; Fan, Zhi-Guo; Zhang, Bo



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

SciTech Connect

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

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



Autoantibodies to low-density-lipoprotein-receptor-related protein 2 (LRP2) in systemic autoimmune diseases  

PubMed Central

We previously reported that autoantibodies (autoAbs) to the main epitope on CD69 reacted to its homologous amino acid sequence in low-density-lipoprotein-receptor-related protein 2 (LPR2), a multiligand receptor for protein reabsorption. In this study, we have investigated the prevalence, autoepitope distribution, and clinical significance of the autoAbs to LRP2 in patients with systemic autoimmune diseases. Using six recombinant proteins (F2–F7) for LRP2 and one for CD69, we detected autoAbs to LRP2 in sera of patients with rheumatoid arthritis (RA), systemic lupus erythematosus, Behçet's disease, systemic sclerosis, and osteoarthritis and then mapped autoepitopes by Western blotting. The autoAbs to LRP2 were detected in 87% of the patients with rheumatoid arthritis, 40% of those with systemic lupus erythematosus, 35% of those with systemic sclerosis, 15% of those with osteoarthritis, and 3% of those with Behçet's disease. Multiple epitopes on LRP2 were recognized by most of the anti-LRP2+ serum samples. All of the tested anti-CD69 autoAb+ samples reacted to LRP2-F3 containing the homologous sequence to the main epitope of CD69; however, only 38% of the anti-LRP2-F3+ samples reacted to CD69. Clinically, the existence of the autoAbs to LRP2-F4, -F5, and -F6 correlated with the presence of proteinuria in RA. This study revealed that LRP2 is a major autoantigen in RA. The autoAbs to LRP2 are probably produced by the antigen-driven mechanism and the autoimmunity to LRP2 may spread to include CD69. The anti-LRP2 autoAbs may play pathological roles by inhibiting the reabsorbing function of LRP2. PMID:12723989

Ooka, Seido; Matsui, Toshihiro; Nishioka, Kusuki; Kato, Tomohiro



Polyunsaturated fatty acids reduce insulin and very low density lipoprotein levels in broiler chickens.  


An experiment was conducted to study the effect of different dietary fatty acid profiles on plasma levels of insulin, very low density lipoproteins (VLDL), cholesterol, and glucose. Diets with four types of fat (tallow, olive, sunflower, and linseed oils) at an inclusion level of 10% and a basal diet without additional fat were administered to female broiler chickens. Serum insulin, cholesterol, and plasma VLDL were affected by the different treatments; however, glucose concentrations were similar among treatments. In the fasted state, broilers fed diets with sunflower or linseed oil presented lower levels of insulin and cholesterol with respect to those fed tallow or olive oil (P < 0.05). VLDL in the fasted state was reduced in broilers fed sunflower and linseed oils (P < 0.05) with respect to those fed tallow, olive oil, or the basal diet. Plasma levels of VLDL were only significantly correlated with abdominal fat in birds fed the basal diet, in the fed and in the fasted state, and in those fed linseed oil in the fed state (P < 0.05). Results of this experiment suggest that higher insulin levels in broilers fed diets rich in saturated fatty acids could be related to higher fat deposition. Fat deposition in birds fed high fat diets was not correlated with circulating VLDL, which suggested direct dietary fat deposition, except for birds fed linseed oil diets. Although birds fed linseed oil diets presented lower levels of VLDL than those fed tallow, olive oil, or the basal diet, the higher correlation with abdominal fat suggests that in these birds, fat deposition is more dependent on hepatic VLDL secretion, despite the high dietary fat level. PMID:12872970

Crespo, N; Esteve-Garcia, E



Pathways for oxidation of high-density lipoprotein in human cardiovascular disease.  


The cardioprotective effect of high-density lipoprotein (HDL) is thought to involve, in part, the membrane-associated ATP-binding cassette transporter ABCA1, which clears cholesterol from lipid-laden macrophages in the artery wall. If HDL is unable to interact with this transporter because of oxidative damage, cholesterol clearance is impaired. Important insights into the mechanisms that oxidize proteins in the human artery wall have come from the mass spectrometric (MS) detection of oxidized amino acids that result from specific reaction pathways. Recent MS studies indicate that HDL isolated from patients with cardiovascular disease contains elevated levels of 3-chlorotyrosine and 3-nitrotyrosine, which are two characteristic products of myeloperoxidase (MPO), a heme enzyme secreted by macrophages. MPO-dependent chlorination of apolipoprotein A-I (apoA-I), the major HDL protein, impairs its ability to remove excess cellular cholesterol by the ABCA1 pathway. Tandem MS analysis of apoA-I has demonstrated that this loss of activity is associated with methionine oxidation and chlorination of a single tyrosine residue. Analysis of mutated forms of apoA-I has implicated lysine residues in the regiospecific chlorination of tyrosine. It is further suggested that the tyrosine chlorination and methionine oxidation of apoA-I impairs ABCA1 transport activity. The crystal structure of lipid-free apoA-I suggests a potential mechanism for rendering this protein dysfunctional. Collectively, these observations indicate that MPO oxidatively damages HDL in humans and suggest that oxidation of specific amino acid residues in apoA-I may contribute to atherogenesis by impairing cholesterol efflux from macrophages. PMID:16774039

Shao, Baohai; Oda, Michael N; Vaisar, Tomas; Oram, John F; Heinecke, Jay W



Effect of temperature and phase transition on oxidation resistance of low density lipoprotein.  


The study of the effect of temperature on the kinetics of low density lipoprotein (LDL) oxidation was carried out by measuring the conjugated diene (CD) versus time curves at a fixed LDL concentration (0.1 microM) and at different Cu2+ concentrations (0.5-10 microM) in a wide temperature range, from 10 degrees C to 45 degrees C. The core melting point of the LDL determined with differential scanning calorimetry was 31.1 degrees C. We have demonstrated that temperature exerts a clear effect in the Cu(2+)-mediated LDL oxidation, with a strong decrease in lag time and a notable increase in the rate of propagation. This temperature dependence of lag time and rate of propagation fully obeys the Arrhenius law, suggesting that the core melting point of the LDL has no or only a minor effect on these oxidation indices. The Arrhenius plots of the binding of Cu2+ to LDL, measured by K, gave two breaks suggesting that this value is affected by the core transition of the LDL as well as by structural changes at around 15 degrees C. The mean activation energy during rate of initiation was 13.5 kcal/mol and tended to decrease with increasing Cu2+ concentration. The activation energy in the propagation phase was 10.6 kcal/mol and was independent of Cu2+ concentration. In this work we have also shown that the CD method can be conducted with high reproducibility and that a sucrose-supplemented plasma frozen at -80 degrees C can be used as a source of LDL with an unvarying vitamin E content and reproducible oxidation properties. PMID:8576638

Ramos, P; Gieseg, S P; Schuster, B; Esterbauer, H



Pro- or anti-inflammatory role of apolipoprotein A-1 in high-density lipoproteins?  


Apolipoprotein A-1 (apoA-1) is the principal protein fraction of high-density lipoprotein (HDL), conferring to the latter many of its pleiotropic atheroprotective functions. After its effect on cholesterol efflux, the second most studied feature of apoA-1 is its anti-inflammatory property. In addition, it interferes with lipid peroxidation and innate immune receptors. These anti-inflammatory effects are due to various properties, in particular the ability to inhibit the transendothelial migration of immune cells by reducing integrin expression, to inhibit monocyte activation and cytokine production induced by T-cell contact, to inhibit lipid peroxidation and to interfere with innate immune receptors. Recent studies have demonstrated that during chronic systemic inflammation HDL could lose some of its atheroprotective functions and become dysfunctional or even proinflammatory. Recent evidence suggests that specific post-translational modifications of apoA-1 transform this genuine anti-inflammatory molecule into a proinflammatory one. The structural changes include chlorination, nitration and carbamylation of amino acids by myeloperoxidase, oxidation by reactive carbonyls, as well as glycation. Humoral autoimmunity to apoA-1 and HDL has been reported in populations at high cardiovascular risk and constitutes another emerging mechanism contributing to the loss of functions of apoA-1 and HDL. The fact that in recent trials cholesteryl ester transfer protein inhibitors (torcerapib and dalcetrapib) have unfortunately failed to prevent cardiovascular disease despite increasing cholesterol efflux in vitro and HDL levels in vivo, further highlights the clinical importance of understanding the mechanisms driving apoA-1 and HDL towards pro- or anti-inflammatory molecules. These findings should not affect current dyslipidaemia management guidelines. PMID:23740387

Vuilleumier, Nicolas; Dayer, Jean-Michel; von Eckardstein, Arnold; Roux-Lombard, Pascale



Systemic Free Fatty Acid Disposal Into Very Low-Density Lipoprotein Triglycerides  

PubMed Central

We measured the incorporation of systemic free fatty acids (FFA) into circulating very low-density lipoprotein triglycerides (VLDL-TGs) under postabsorptive, postprandial, and walking conditions in humans. Fifty-five men and 85 premenopausal women with BMI 18–24 (lean) and 27–36 kg/m2 (overweight/obese) received an intravenous bolus injection of [1,1,2,3,3-2H5]glycerol (to measure VLDL-TG kinetics) and either [1-14C]palmitate or [9,10-3H]palmitate to determine the proportion of systemic FFA that is converted to VLDL-TG. Experiments started at 0630 h after a 12-h overnight fast. In the postabsorptive protocol, participants rested and remained fasted until 1330 h. In the postprandial protocol, volunteers ingested frequent portions of a fat-free smoothie. In the walking protocol, participants walked on a treadmill for 5.5 h at ?3× resting energy expenditure. Approximately 7% of circulating FFA was converted into VLDL-TG. VLDL-TG secretion rates (SRs) were not statistically different among protocols. Visceral fat mass was the only independent predictor of VLDL-TG secretion, explaining 33–57% of the variance. The small proportion of systemic FFA that is converted to VLDL-TG can confound the expected relationship between plasma FFA concentration and VLDL-TG SRs. Regulation of VLDL-TG secretion is complex in that, despite a broad spectrum of physiological FFA concentrations, VLDL-TG SRs did not vary based on different acute substrate availability. PMID:23434937

Koutsari, Christina; Mundi, Manpreet S.; Ali, Asem H.; Patterson, Bruce W.; Jensen, Michael D.



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

PubMed Central

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

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



Low-density lipoprotein receptor-related protein 5 governs Wnt-mediated osteoarthritic cartilage destruction  

PubMed Central

Introduction Wnt ligands bind to low-density lipoprotein receptor–related protein (LRP) 5 or 6, triggering a cascade of downstream events that include ?-catenin signaling. Here we explored the roles of LRP5 in interleukin 1? (IL-1?)- or Wnt-mediated osteoarthritic (OA) cartilage destruction in mice. Methods The expression levels of LRP5, type II collagen, and catabolic factors were determined in mouse articular chondrocytes, human OA cartilage, and mouse experimental OA cartilage. Experimental OA in wild-type, Lrp5 total knockout (Lrp5-/-) and chondrocyte-specific knockout (Lrp5fl/fl;Col2a1-cre) mice was caused by aging, destabilization of the medial meniscus (DMM), or intra-articular injection of collagenase. The role of LRP5 was confirmed in vitro by small interfering RNA–mediated knockdown of Lrp5 or in Lrp5-/- cells treated with IL-1? or Wnt proteins. Results IL-1? treatment increased the expression of LRP5 (but not LRP6) via JNK and NF-?B signaling. LRP5 was upregulated in human and mouse OA cartilage, and Lrp5 deficiency in mice inhibited cartilage destruction. Treatment with IL-1? or Wnt decreased the level of Col2a1 and increased those of Mmp3 or Mmp13, whereas Lrp5 knockdown ameliorated these effects. In addition, we found that the functions of LRP5 in arthritic cartilage were subject to transcriptional activation by ?-catenin. Moreover, Lrp5-/- and Lrp5fl/fl;Col2a1-cre mice exhibited decreased cartilage destruction (and related changes in gene expression) in response to experimental OA. Conclusions Our findings indicate that LRP5 (but not LRP6) plays an essential role in Wnt/?-catenin-signaling-mediated OA cartilage destruction in part by regulating the expression levels of type II collagen, MMP3, and MMP13. PMID:24479426



Mimicry of High-Density Lipoprotein: Functional Peptide-Lipid Nanoparticles Based on Multivalent Peptide Constructs  

PubMed Central

We describe an approach for engineering peptide–lipid nanoparticles that function similarly to high-density lipoprotein (HDL). Branched, multivalent constructs, bearing multiple 23- or 16-amino-acid peptides, were designed, synthesized and combined with phospholipids to produce nanometer-scale discoidal HDL-like particles. A variety of biophysical techniques were employed to characterize the constructs, including size exclusion chromatography, analytical ultracentrifuge sedimentation, circular dichroism, transmission electron microscopy, and fluorescence spectroscopy. The nanoparticles functioned in vitro (human and mouse plasma) and in vivo (mice) to rapidly remodel large native HDLs into small lipid-poor HDL particles, which are key acceptors of cholesterol in reverse cholesterol transport. Fluorescent labeling studies showed that the constituents of the nanoparticles readily distributed into native HDLs, such that the peptide constructs coexisted with apolipoprotein A-I, the main structural protein in HDLs. Importantly, nanolipid particles containing multivalent peptides promoted efficient cellular cholesterol efflux and were functionally superior to those derived from monomeric peptides. The multivalent peptide-lipid nanoparticles were also remarkably stable toward enzymatic digestion in vitro and displayed long half-lives and desirable pharmacokinetic profiles in mice, providing a real practical advantage over previously studied linear or tandem helical peptides. Encouragingly, a two-week exploratory efficacy study in a widely used animal model for atherosclerosis research (LDLr-null mice) using nanoparticles constructed from a trimeric peptide demonstrated an exceptional 50% reduction in the plasma total cholesterol levels compared to the control group. Altogether, the studies reported here point to an attractive avenue for designing synthetic, HDL-like nanoparticles, with potential for treating atherosclerosis. PMID:23978057

Zhao, Yannan; Imura, Tomohiro; Leman, Luke J.; Curtiss, Linda K.; Maryanoff, Bruce E.; Ghadiri, M. Reza



Freezing canine sperm: comparison of semen extenders containing Equex and LDL (Low Density Lipoproteins).  


Chicken egg yolk is held as an excellent cryoprotective agent for freezing canine semen. Recent advances have enabled the extraction of low density lipoproteins from egg yolk, which are responsible for the cryoprotective abilities of the latter. The objective of this article was to compare 3 semen extenders for freezing canine semen: 2 containing egg yolk (Tris egg yolk and Equex STAMP) and one containing 6% LDL. After freezing and thawing 20 ejaculates from 5 different dogs, the 6% LDL extender produced 50% mobile spermatozoa, compared with 48% with the Equex extender and 27.7% with the extender containing egg yolk alone (EY). In vitro functional tests demonstrated that the integrity of the plasma membrane (hypoosmotic test) was respected in 65-66% of spermatozoa as a function of the extender; DNA integrity was respected in more than 97% of the spermatozoa. The Equex extender provided superior acrosome integrity (FITC/PSA test): 68.4% compared with 55.1% with LDL and 53.3% with egg yolk. However, the 6% LDL extender resulted in fewer spermatozoal anomalies (Spermac test), with 54.6% normal spermatozoa compared to 53.6% for Equex and 53.3% with the egg yolk. All six of the bitches inseminated artificially via the intra-uterine route (Scandinavian technique) using semen frozen in the 6% LDL extender became pregnant. The LDL extender resulted in percentages of mobile spermatozoa and movement characteristics that were as good if not better than those obtained with the reference extenders following thawing. The 6% LDL extender appears to have the same cryoprotective qualities as the reference diluent, Equex STAMP. PMID:20153943

Bencharif, Djemil; Amirat-Briand, Lamia; Garand, Annabelle; Anton, Marc; Schmitt, Eric; Desherces, Serge; Delhomme, Guy; Langlois, Marie-Laure; Barrière, Paul; Destrumelle, Sandrine; Vera-Munoz, Oscar; Tainturier, Daniel



Measurement of very low density and low density lipoprotein apolipoprotein (Apo) B-100 and high density lipoprotein Apo A-I production in human subjects using deuterated leucine. Effect of fasting and feeding.  

PubMed Central

Six normolipidemic male subjects, after an 8-h overnight fast, were given a bolus injection and then a 15-h constant intravenous infusion of [D3]L-leucine. Subjects were studied in the fasted state and on a second occasion in the fed state (small, physiological meals were given every hour for 15 h). Apolipoproteins were isolated by preparative gradient gel electrophoresis from plasma lipoproteins separated by sequential ultracentrifugation. Incorporation of [D3]L-leucine into apolipoproteins was monitored by negative ionization, gas chromatography-mass spectrometry. Production rates were determined by multiplying plasma apolipoprotein pool sizes by fractional production rates (calculated as the rate of isotopic enrichment [IE] of each protein as a fraction of IE achieved by VLDL (d less than 1.006 g/ml) apo B-100 at plateau. VLDL apo B-100 production was greater, and LDL (1.019 less than d less than 1.063 g/ml) apo B-100 production was less in the fed compared with the fasted state (9.9 +/- 1.7 vs. 6.4 +/- 1.7 mg/kg per d, P less than 0.01, and 8.9 +/- 1.2 vs. 13.1 +/- 1.2 mg/kg per d, P less than 0.05, respectively). No mean change was observed in high density lipoprotein apo A-I production. We conclude that: (a) this stable isotope, endogenous-labeling technique, for the first time allows for the in vivo measurement of apolipoprotein production in the fasted and fed state; and (b) since LDL apo B-100 production was greater than VLDL apo B-100 production in the fasted state, this study provides in vivo evidence that LDL apo B-100 can be produced independently of VLDL apo B-100 in normolipidemic subjects. Images PMID:2107210

Cohn, J S; Wagner, D A; Cohn, S D; Millar, J S; Schaefer, E J



Effect of the Combination of Methyltestosterone and Esterified Estrogens Compared with Esterified Estrogens Alone on Apolipoprotein CIII and Other Apolipoproteins in Very Low Density, Low Density, and High Density Lipoproteins in Surgically Postmenopausal Women  

Microsoft Academic Search

Androgens are known to lower plasma triglycerides, an in- dependent risk factor for coronary heart disease (CHD). Tri- glycerides are carried in plasma on very low density (VLDL) and low density (LDL) lipoprotein particles. Apolipoprotein CIII (apoCIII), a strong predictor of CHD, impairs the metab- olism of VLDL and LDL, contributing to increased triglycer- ides. The objective of this study



Elevated Low-Density Lipoprotein in Alzheimer's Disease Correlates with Brain A? 1–42 Levels  

Microsoft Academic Search

Sera obtained in the immediate postmortem from 100 individuals, 64 neuropathologically diagnosed Alzheimer's disease (AD) cases and 36 nondemented controls, were analyzed for cholesterol, lipoproteins, apolipoproteins (Apo), and triglycerides. All individuals were ApoE genotyped, and the amounts of A? (N-40 and N-42) in cerebral cortex of AD and control subjects were determined. When compared to controls, AD individuals had significantly

Yu-Min Kuo; Mark R. Emmerling; Charles L. Bisgaier; Arnold D. Essenburg; Heather C. Lampert; Denise Drumm; Alex E. Roher



Influence of Native and Hypochlorite-Modified Low-Density Lipoprotein on Gene Expression in Human Proximal Tubular Epithelium  

PubMed Central

Inflammatory infiltrates can modify (lipo)proteins via hypochlorous acid/hypochlorite (HOCl/OCl?) an oxidant formed by the myeloperoxidase-H2O2-halide system. These oxidatively modified proteins emerge in tubuli in some proteinuric and interstitial diseases. Human proximal tubular cells (HK-2) were used to confirm the hypothesis of detrimental and differential impact of HOCl-modified low density lipoprotein (HOCl-LDL), an in vivo occurring lipoprotein modification exerting proatherogenic and proinflammatory capacity. HOCl-LDL showed dose-dependent antiproliferative effects in HK-2 cells. Small dedicated cDNA macroarrays were used to identify differentially regulated genes. A rapid increase in the expression of genes involved in reactive oxygen species metabolism and cell stress, eg, heme oxygenase-1, thioredoxin reductase, cytochrome b5 reductase, Gadd 153, amino acid transporter E16, and HSP70 was found after HOCl-LDL treatment of HK-2 cells. In parallel, genes involved in tissue remodeling and inflammation eg, CTGF, VCAM-1, IL-1?, MMP7, and VEGF were up-regulated. Quantitative RT-PCR verified differential expression of a subset of these genes in microdissected tubulointerstitia from patients with acute tubular damage, progressive proteinuric renal disease, and membranous glomerulonephritis (with declining renal function), but not in stable patients with proteinuria caused by minimal change disease. The demonstration of selective up-regulation of a subgroup of genes if proteinuria is accompanied by the presence of HOCl-modified (lipo)proteins support the potential pathophysiological role of the myeloperoxidase-H2O2-halide system and HOCl-LDL in renal disease. PMID:15161651

Porubsky, Stefan; Schmid, Holger; Bonrouhi, Mahnaz; Kretzler, Matthias; Malle, Ernst; Nelson, Peter J.; Grone, Hermann-Josef



Biochemical and functional characterization of charge-defined subfractions of high-density lipoprotein from normal adults.  


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

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



Allele-specific expression of the low density lipoprotein receptor gene  

SciTech Connect

Approximately 60% of familial hypercholesterolemia (FH) in French Canadians is due to a > 10 kb deletion of the promoter region of the gene encoding the low density lipoprotein (LDL) receptor (LDL-R), allowing determination of the influence of a single LDL-R allele on phenotypic expression of FH. Normal allele haplotypes of approximately 250 heterozygotes were determined with 7 RFLPs. In vitro maximal LDL-R activity of blood lymphocytes from a subset of approximately 150 heterozygotes, measured by immunocytofluorometry, was significantly higher (20 to 30%) in subjects with LDL-R normal allele haplotype G (n=11), and O (n=7) compared to the most frequent haplotype F (n=43), while no differences were observed among F, E (n=11), and the 2 other most prevalent haplotypes (n=43). LDL-R mRNA in these lymphocytes was significantly elevated 2.3-, 1.7-, and 1.8- fold, in G, O, and E, respectively, compared to F, while no significant differences were apparent between F and the other two most frequent haplotyes. Large interindividual variability in lymphocyte LDL-R mRNA levels and activity was observed even among subjects with the same LDL-R normal allele haplotype. However, maximally induced lymphocyte LDL-R mRNA levels correlated poorly with levels measured in freshly isolated cells (n=14). Relative to haplotype F (n=47 women (W), 39 men (M)), mean plasma LDL cholesterol levels adjusted for age and apolipoprotein E genotype were 5-10% lower in men and women with haplotypes G (n=16 W, 12 M) and O (n=8 W, 6 M), and 20% lower in 7 W with haplotype E. These results suggest that (1) normal LDL-R allele haplotype G and O may contain sequence variations which confer relatively high gene expression and (2) environmental and genetic influences other than the LDL-R gene contribute substantially to variability in LDL-R expression and plasma LDL cholesterol levels in French Canadian FH heterozygotes.

Minnich, A.; Lussier-Cacan, S.; Roy, M. [Clincial Research Institute of Montreal, Quebec (Canada)



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

PubMed Central

The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease (CVD), and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association (GWA) scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p < 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly Long Life Family Study (LLFS) subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in Encyclopedia of DNA Elements (ENCODE); however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region. PMID:24917880

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



Relationship between oxidized low-density lipoprotein antibodies and obesity in different glycemic situations  

PubMed Central

Background Autoantibodies to oxidized low-density lipoprotein (oxLDL) are a heterogeneous group of antibodies that are controversially discussed to be either pathogenic or protective. Biochemical and anthropometric measurements correlated with increased levels of these antibodies are also controversial, especially in conditions of impaired glucose tolerance and type 2 diabetes mellitus. The present study was conducted to evaluate levels of oxLDL antibodies and their correlation with obesity in different glycemic situations. Methods Two hundred and seventy-four adult males were classified into three subgroups: group 1 (n=125), comprising a control group of nondiabetic subjects; group 2 (n=77), comprising subjects with impaired glucose tolerance; and group 3 (n=72), comprising patients with type 2 diabetes mellitus. Body mass index was calculated, and measurement of oxLDL and oxLDL antibodies was performed. Results Higher mean concentrations of oxLDL were found in the type 2 diabetes mellitus and impaired glucose tolerance groups (143.5±21.9 U/L and 108.7±23.7 U/L, respectively). The mean value for the control group was 73.5±27.5 U/L (P<0.001). Higher mean concentrations of anti-oxLDL antibodies were observed in the type 2 diabetes mellitus and impaired glucose tolerance groups (55.7±17.8 U/L and 40.4±17.6 U/L, respectively). The mean value for the control group was 20.4±10 U/L (P<0.001). Levels of anti-oxLDL antibodies were found to be positively and significantly correlated with body mass index in the control group (r=0.46), impaired glucose tolerance (r=0.51), type 2 diabetes mellitus group (r=0.46), and in the whole study population (r=0.44; P<0.001). Conclusion Anti-oxLDL antibody levels were increased in subjects with type 2 diabetes mellitus and impaired glucose tolerance and were positively correlated with obesity and body mass index. PMID:25368528

Babakr, Abdullatif Taha; Elsheikh, Osman Mohamed; Almarzouki, Abdullah A; Assiri, Adel Mohamed; Abdalla, Badr Eldin Elsonni; Zaki, Hani Yousif; Fatani, Samir H; NourEldin, EssamEldin Mohamed



High-density lipoproteins induce a rapid and transient release of Ca2+ in cultured fibroblasts.  


Several different cell types showed increased rates of proliferation and cholesterol mobilization in response to treatment with high-density lipoprotein (HDL). This would suggest that one main function of HDL is the activation of signal pathways in cells. In the current study we have used the fluorescent indicator fura-2 to monitor the level of cytosolic Ca2+ ([Ca2+]i) in human skin fibroblasts. Exposure of subconfluent as well as confluent fibroblasts to HDL3 (20-60 micrograms/ml) resulted in a rapid and transient increase in [Ca2+]i. Sequential additions of HDL3 resulted in diminished rises in [Ca2+]i. The transient rise in [Ca2+]i was observed with HDL prepared from plasma either by conventional ultracentrifugation or by precipitation with dextran sulphate. Chelation of the extracellular Ca2+ with EGTA prior to the addition of HDL3 did not prevent the HDL3-induced rise in [Ca2+]i, suggesting that the mobilized Ca2+ was derived mainly from intracellular stores. Covalent modification of the apoproteins of HDL3 with dimethyl suberimidate or tetranitromethane did not inhibit the HDL3-induced rise in [Ca2+]i. This indicates that the binding of HDL3 to cell surface receptors may not be necessary for the mobilization of intracellular Ca2+. Moreover, the Ca(2+)-releasing effect of HDL3 was not inhibited by the presence of albumin (1%, w/v) in the extracellular medium, suggesting that non-esterified fatty acids were not the cause of the increased [Ca2+]i. The exposure of fibroblasts to lysophosphatidic acid, a potent mitogen and Ca(2+)-releasing agent, before addition of HDL3 completely inhibited the HDL3-induced rise in [Ca2+]i. Furthermore, phorbol 12-myristate 13-acetate blocked the HDL3-induced rise in [Ca2+]i. The results of this study imply that exposure of cells to HDL generates an intracellular signal which is induced by a component of the lipid fraction. PMID:1930148

Pörn, M I; Akerman, K E; Slotte, J P



Impact of body composition on very-low-density lipoprotein-triglycerides kinetics.  


Upper body obese (UBO) subjects have greater cardiovascular disease risk than lower body obese (LBO) or lean subjects. Obesity is also associated with hypertriglyceridemia that may involve greater production and impaired removal of very-low-density lipoprotein (VLDL)-triglycerides (TG). In these studies, we assessed the impact of body composition on basal VLDL-TG production, VLDL-TG oxidation, and VLDL-TG storage. VLDL-TG kinetics were assessed in 10 UBO, 10 LBO, and 10 lean women using a bolus injection of [1-(14)C]VLDL-TG. VLDL-TG oxidation was measured by (14)CO(2) production (hyamine trapping) and VLDL-TG adipose tissue storage by fat biopsies. Insulin sensititvity was assessed by the hyperinsulinemic-euglycemic clamp technique and body composition by dual X-ray absorptiometry in combination with computed tomography. Hepatic VLDL-TG production was significantly greater in UBO than in lean women [(mumol/min) UBO: 64.8 (SD 40.0) vs. LBO: 42.5 (SD 25.6) vs. lean: 31.8 (SD 13.3), P = 0.04], whereas VLDL-TG oxidation was similar in the three groups and averaged 20% of resting energy expenditure [(mumol/min) UBO: 38.3 (SD 26.5) vs. LBO: 23.5 (SD 13.5) vs. lean: 21.1 (SD 9.7), P = 0.09]. In UBO women, more VLDL-TG was deposited in upper body subcutaneous fat [VLDL-TG redeposition in abdominal adipose tissue (mumol/min): UBO: 5.0 (SD 2.9) vs. LBO: 4.0 (SD 3.2) vs. lean: 1.3 (SD 1.0), ANOVA P = 0.01]; in LBO women, more VLDL-TG was deposited in femoral fat [VLDL-TG redeposition in femoral adipose tissue (mumol/min): UBO: 5.1 (SD 3.1) vs. LBO: 5.8 (SD 4.3) vs. lean: 2.3 (SD 1.5), ANOVA P = 0.04]. Only a small proportion of VLDL-TG (8-16%) was partitioned into redeposition in either group. We found that elevated VLDL-TG production without concomitant increased clearance via oxidation and adipose tissue redeposition contributes to hypertriglyceridemia in UBO women. PMID:18984851

Gormsen, Lars C; Nellemann, Birgitte; Sørensen, Lars P; Jensen, Michael D; Christiansen, Jens S; Nielsen, Søren



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

NASA Astrophysics Data System (ADS)

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

Damiano, Marina Giacoma


High-Density Lipoproteins Potentiate ?1-Antitrypsin Therapy in Elastase-Induced Pulmonary Emphysema.  


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

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



Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor-deficient atherosclerosis  

SciTech Connect

The metabolism of infused /sup 111/In-labeled phospholipid liposomes was examined in Watanabe heritable hyperlipidemic (WHHL) rabbits, which lack low density lipoprotein (LDL) receptors, and in normal control rabbits. The half-times (t/sub 1/2/) for clearance of /sup 111/In and excess phospholipid from plasma were 20.8 +/- 0.9 hr and 20.3 +/- 4.6 hr in WHHL and 20.0 +/- 0.8 hr and 19.6 +/- 2.2 hr in the normal rabbits. By 6 hr postinfusion, the plasma concentration of unesterified cholesterol increased by 2.2 +/- 0.23 mmol/liter in WHHL and 2.1 +/- 0.04 mmol/liter in normal rabbits, presumably reflecting mobilization of tissue sores. Disappearance of excess plasma cholesterol was > 90% complete in both groups of rabbits by 70 hr postinfusion. By quantitative ..gamma.. camera imaging, hepatic trapping of /sup 111/In-labeled liposomes over time was indistinguishable between the two groups. At autopsy, the liver was the major organ of clearance. Aortic uptake of /sup 111/In was < 0.02%. Thus, mobilization of cholesterol and hepatic uptake of phospholipid liposomes do not require LDL receptors. Because phospholipid infusions produce rapid substantial regression of atherosclerosis in genetically normal animals, the results suggest that phospholipid liposomes or triglyceride phospholipid emulsions (e.g., Intralipid) might reduce atherosclerosis in WHHL rabbits and in humans with familial hypercholesterolemia.

Williams, K.J.; Vallabhajosula, S.; Rahman, I.U.; Donnelly, T.M.; Parker, T.S.; Weinrauch, M.; Goldsmith, S.J.



Determination of the respective density distributions of low-and high-density lipoprotein particles in bovine plasma  

E-print Network

particles in bovine plasma and lymph by immunoassay of apoproteins A-I and B S Auboiron D Durand PM Laplaud2-Genes Champanelle, France In our preliminary studies dealing with bovine plasma lipoproteins, we suggest- ed on a heparin!epharose column showed the presence of 2 forms of HDL containing apoprotein (apo) A-I and one form

Paris-Sud XI, Université de


Effect of dietary trans fatty acids on high-density and low-density lipoprotein cholesterol levels in healthy subjects  

Microsoft Academic Search

BACKGROUND. Fatty acids that contain a trans double bond are consumed in large amounts as hydrogenated oils, but their effects on serum lipoprotein levels are unknown. METHODS. We placed 34 women (mean age, 26 years) and 25 men (mean age, 25 years) on three mixed natural diets of identical nutrient composition, except that 10 percent of the daily energy intake

Ronald P. Mensink; Martijn B. Katan



Serum concentration of small dense low-density lipoprotein-cholesterol during oral glucose tolerance test and oral fat tolerance test  

Microsoft Academic Search

BackgroundSmall dense low-density lipoprotein (sdLDL) is well known as an atherogenic lipoprotein. We developed a new assay to measure serum concentration of sdLDL-cholesterol (sdLDLC). Using this assay, we reported a unique circadian rhythm of sdLDLC. We determined whether a glucose intake and\\/or a fat intake affects on serum sdLDLC concentration and determined the modulators of serum sdLDLC concentration.

Kyoko Ogita; Masumi Ai; Akira Tanaka; Yasuki Ito; Tsutomu Hirano; Gen Yoshino; Kentaro Shimokado



Cholesteryl ester transfer protein gene haplotypes, plasma high-density lipoprotein levels and the risk of coronary heart disease  

Microsoft Academic Search

High-density lipoprotein cholesterol (HDL-C) is a known inverse predictor of coronary heart disease (CHD) and is thus a potential\\u000a therapeutic target. Cholesteryl ester transfer protein (CETP) is a key protein in HDL-C metabolism such that elevated CETP\\u000a activity is associated with lower HDL-C. Currently available HDL-C raising drugs are relatively ineffective and evidence suggesting\\u000a the role of CETP in HDL-C

Pamela A. McCaskie; John P. Beilby; Caroline M. L. Chapman; Joseph Hung; Brendan M. McQuillan; Peter L. Thompson; Lyle J. Palmer



The effect of a low-fat, high-carbohydrate diet on serum high density lipoprotein cholesterol and triglyceride  

Microsoft Academic Search

Objective: To determine whether substituting carbohydrate for saturated fat has any adverse effects on serum high density lipoprotein (HDL) cholesterol and triglycerides in free-living individuals.Design: Randomised crossover trial.Setting: General community.Subjects: Volunteer sample of 38 healthy free-living men with mean (s.d.) age 37 (7) y, moderately elevated serum total cholesterol 5.51 (0.93) mmol\\/l and body mass index 26.0 (3.6) kg\\/m2.Interventions: Participants

ML Turley; CM Skeaff; JI Mann; B Cox



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

NASA Astrophysics Data System (ADS)

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

Singh, Bal R.; Poirier, Michelle A.



Effects of preincubation of primary monolayer cultures of rat hepatocytes with low- and high-density lipoproteins on the subsequent binding and metabolism of human low-density lipoprotein.  

PubMed Central

1. There are two distinct binding sites (Site 1 and Site 2) for human low-density lipoprotein (LDL) on rat hepatocytes in monolayer culture [Salter, Saxton & Brindley (1986) Biochem. J. 240, 549-557]. 2. Binding of 125I-LDL to Site 1, but not to Site 2, is up-regulated between 20 and 44 h in culture by preincubation of the cells with human high-density lipoprotein 3 (HDL3). 3. A similar preincubation with HDL2 had no significant effect on binding to either site. 4. Preincubation with human LDL led to a partial down-regulation of subsequent binding of 125I-LDL to Site 1. Since binding after incubation with LDL was measured at 37 degrees C, binding to Site 2 could not be distinguished from LDL that had been internalized by the cells. 5. Hepatocytes were shown to degrade 125I-LDL, resulting in the accumulation of [125I]iodotyrosine in the medium. Evidence was found that iodotyrosine may be further degraded by deiodinase produced by the cells. 6. Regulation of binding to Site 1 by preincubation with LDL or HDL3 was found to lead to a parallel regulation of LDL degradation. 7. It is concluded that rat hepatocytes not only bind but also metabolize human LDL and that these processes are under metabolic regulation. PMID:3689356

Salter, A M; Bugaut, M; Saxton, J; Fisher, S C; Brindley, D N



Characterization of the calcium site in two complement-like domains from the low-density lipoprotein receptor-related protein (LRP) and comparison with a repeat from the low-density lipoprotein receptor.  


Calcium is required for the binding and endocytosis of protein ligands by the low-density lipoprotein receptor-related protein (LRP) and other members of the low-density lipoprotein (LDL) receptor family. Calcium binding sites are thought to be present in the complement-like repeats that occur in clusters in all members of this receptor family. We have expressed two such complement-like repeats, CR3 and CR8, from an alpha2-macroglobulin-proteinase ligand binding region of LRP, as well as repeat 1 from the LDL receptor and examined the metal binding properties and resulting structural changes of these three repeats using changes in tryptophan and terbium fluorescence and perturbation of [1H-15N]-HSQC NMR spectra of the 15N-labeled domains from LRP. We found that all three domains contain a tight calcium binding site at physiological pH and that calcium binding results in a major structural rigidification. Changes in tryptophan fluorescence and tryptophan-sensitized terbium fluorescence indicate that the calcium binding sites are located in homologous regions in all of the repeats. Differences in the details of the perturbations, as well as in the pH dependence of calcium binding, show, however, that each metal site is distinct. PMID:9836596

Dolmer, K; Huang, W; Gettins, P G



Effect of improving glycemic control on low-density lipoprotein particle size in type 2 diabetes  

Microsoft Academic Search

The current study sought to assess the effect of improving glycemic control in type 2 diabetes on the components of diabetic dyslipidemia, especially low-denisty lipoprotein (LDL) size. A total of 33 type 2 diabetic patients (48.5% women, age 59.6 ± 11.1 years, body mass index [BMI] 28.9 ± 4.9, diabetes duration 6 [0 to 40] years, 40.7% on insulin) were

Ana Mar??a Wägner; Oscar Jorba; Mercedes Rigla; Rosa Bonet; Alberto de Leiva; Jordi Ordóñez-Llanos; Antonio Pérez



High-density lipoprotein cholesterol levels in middle-school children: association with cardiovascular risk factors and lifestyle behaviors.  


To examine factors associated with low high-density lipoprotein cholesterol (HDL-C) levels among middle school children. HDL-C levels were the primary outcome of interest. A total of 1,104 middle-school children (mean age 11.6 years, 51.2% female) were included in this analysis, of whom 177 (16%) had an HDL-C level ?40 mg/dL. More than half of those with low HDL-C were overweight or obese (62.2%) and had greater systolic and diastolic blood pressure, triglyceride (TRG) levels, and low-density lipoprotein cholesterol levels compared with children with an HDL-C level >40 mg/dL. Among those with an HDL-C ? 40 mg/dL, 35% also had body mass index ?85% and TRG levels ?150 mg/dL. Exercise habits were significantly associated with HDL-C level, whereas sedentary behaviors, such as screen time, were not significantly associated with HDL-C level. Fruit and vegetable intake was also not significantly associated with HDL-C level. Children with low HDL-C levels are more likely to be overweight and to have other physiological indicators of increased cardiovascular risk. Further research is needed to determine if school-based interventions can result in long-term improvements in HDL-C. PMID:24132620

Flynn, Shannon E; Gurm, Roopa; DuRussel-Weston, Jean; Aaronson, Susan; Gakenheimer, Lindsey; Smolarski, Joseph; Simhaee, Daniel; Corriveau, Nicole; Goldberg, Caren; Eagle, Taylor; Rao, Ravi M; Eagle, Kim A; Jackson, Elizabeth A



Antagonism of Secreted PCSK9 Increases Low Density Lipoprotein Receptor Expression in HepG2 Cells  

SciTech Connect

PCSK9 is a secreted protein that degrades low density lipoprotein receptors (LDLRs) in liver by binding to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. It is not known whether PCSK9 causes degradation of LDLRs within the secretory pathway or following secretion and reuptake via endocytosis. Here we show that a mutation in the LDLR EGF-A domain associated with familial hypercholesterolemia, H306Y, results in increased sensitivity to exogenous PCSK9-mediated cellular degradation because of enhanced PCSK9 binding affinity. The crystal structure of the PCSK9-EGF-A(H306Y) complex shows that Tyr-306 forms a hydrogen bond with Asp-374 in PCSK9 at neutral pH, which strengthens the interaction with PCSK9. To block secreted PCSK9 activity, LDLR (H306Y) subfragments were added to the medium of HepG2 cells stably overexpressing wild-type PCSK9 or gain-of-function PCSK9 mutants associated with hypercholesterolemia (D374Y or S127R). These subfragments blocked secreted PCSK9 binding to cell surface LDLRs and resulted in the recovery of LDLR levels to those of control cells. We conclude that PCSK9 acts primarily as a secreted factor to cause LDLR degradation. These studies support the concept that pharmacological inhibition of the PCSK9-LDLR interaction extracellularly will increase hepatic LDLR expression and lower plasma low density lipoprotein levels.

McNutt, Markey C.; Kwon, Hyock Joo; Chen, Chiyuan; Chen, Justin R.; Horton, Jay D.; Lagace, Thomas A.; (USMC); (UTSMC)



Endothelial NOS-dependent activation of c-Jun NH(2)- terminal kinase by oxidized low-density lipoprotein  

NASA Technical Reports Server (NTRS)

Oxidized low-density lipoprotein (oxLDL) is known to activate a number of signal transduction pathways in endothelial cells. Among these are the c-Jun NH(2)-terminal kinase (JNK), also known as stress-activated protein kinase, and extracellular signal-regulated kinase (ERK). These mitogen-activated protein kinases (MAP kinase) determine cell survival in response to environmental stress. Interestingly, JNK signaling involves redox-sensitive mechanisms and is activated by reactive oxygen and nitrogen species derived from both NADPH oxidases, nitric oxide synthases (NOS), peroxides, and oxidized low-density lipoprotein (oxLDL). The role of endothelial NOS (eNOS) in the activation of JNK in response to oxLDL has not been examined. Herein, we show that on exposure of endothelial cells to oxLDL, both ERK and JNK are activated through independent signal transduction pathways. A key role of eNOS activation through a phosphatidylinositol-3-kinase-dependent mechanism leading to phosphorylation of eNOS is demonstrated for oxLDL-dependent activation of JNK. Moreover, we show that activation of ERK by oxLDL is critical in protection against the cytotoxicity of oxLDL.

Go, Y. M.; Levonen, A. L.; Moellering, D.; Ramachandran, A.; Patel, R. P.; Jo, H.; Darley-Usmar, V. M.



Morphological evidence that high density lipoproteins are not internalized by steroid-producing cells during in situ organ perfusion  

SciTech Connect

Although it is clear that high density lipoproteins (HDL) can support steroidogenesis in several rat cell systems, questions still arise as to how HDL are processed by cells. In particular, it is not yet clear whether HDL are internalized by a pathway similar to that used for low density lipoproteins. This issue was examined in the present study using the luteinized ovaries of hormone-primed immature rats in an in situ perfusion system. Ovaries were perfused for 2-120 min with /sup 125/I-labeled human or rat HDL and processed for autoradiographic studies at the light and electron microscopic level, or homogenized and used for isolation of subcellular membranes. The results show that the luteal cells of this tissue bind both human and rat HDL with great specificity. Moreover, the intact HDL particle does not appear to be internalized by the luteal cell during the period of perfusion: i.e., the protein moiety of the labeled HDL remains associated with the plasma membrane at all times. Evidence from the autoradiographs suggest, however, that with time, an increasing proportion of the plasma membrane-bound protein is associated with inverted microvilli, which are embedded within the cytoplasm and make close contact with structures of the interior of the cell. We speculate that HDL-cholesterol may be transferred at such sites.

Reaven, E.; Chen, Y.D.; Spicher, M.; Azhar, S.



Reduced very-low-density lipoprotein fractional catabolic rate in apolipoprotein C1-deficient mice.  

PubMed Central

The function of apolipoprotein (apo) C1 in vivo is not clearly defined. Because transgenic mice overexpressing human apoC1 show elevated triacylglycerol (TG) levels [Simonet, Bucay, Pitas, Lauer and Taylor (1991) J. Biol. Chem. 266, 8651-8654], an as yet unknown role for apoC1 in TG metabolism has been suggested. Here we investigated directly the effect of the complete absence of apoC1 on very-low-density lipoprotein (VLDL)-TG lipolysis, clearance and production, by performing studies with the previously generated apoC1-deficient mice. On a sucrose-rich, low fat/low cholesterol (LFC) diet, apoC1-deficient mice accumulate in their circulation VLDL particles, which contain relatively lower amounts of lipids when compared with VLDL isolated from control mice. Lipolysis assays in vitro on VLDL from apoC1-deficient and control mice showed no differences in apparent K(m) and Vmax values (0.27 +/- 0.06 versus 0.24 +/- 0.03 mmol of TG/litre and 0.40 +/- 0.03 versus 0.36 +/- 0.03 mmol of non-esterified fatty acid (NEFA)/min per litre respectively). To correct for potential differences in the size of the VLDL particles, the resulting K(m) values were also expressed relative to apoB concentration. Under these conditions apoC1-deficient VLDL displayed a lower, but not significant, K(m) value when compared with control VLDL (3.44 +/- 0.71 versus 4.44 +/- 0.52 mmol of TG2/g apoB per litre). VLDL turnover studies with autologous injections of [3H]TG-VLDL in vivo showed that the VLDL fractional catabolic rate (FCR) was decreased by up to 50% in the apoC1-deficient mice when compared with control mice (10.5 +/- 3.4 versus 21.0 +/- 1.2/h of pool TG). No significant differences between apoC1-deficient and control mice were observed in the hepatic VLDL production estimated by Triton WR139 injections (0.19 +/- 0.02 versus 0.21 +/- 0.05 mmol/h of TG per kg) and in the extra-hepatic lipolysis of VLDL-TG (4.99 +/- 1.62 versus 3.46 +/- 1.52/h of pool TG) in vivo. Furthermore, [125I]VLDL-apoB turnover experiments in vivo also showed a 50% decrease in the FCR of VLDL in apoC1-deficient mice when compared with control mice on the LFC diet (1.1 +/- 0.3 versus 2.1 +/- 0.1/h of pool apoB). When mice were fed a very high fat/high cholesterol (HFC) diet, the VLDL-apoB FCR was further decreased in apoC1-deficient mice (0.4 +/- 0.1 versus 1.4 +/- 0.4/h of pool apoB). We conclude that, in apoC1-deficient mice, the FCR of VLDL is reduced because of impaired uptake of VLDL remnants by hepatic receptors, whereas the production and lipolysis of VLDL-TG is not affected. PMID:9020879

Jong, M C; van Ree, J H; Dahlmans, V E; Frants, R R; Hofker, M H; Havekes, L M



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

PubMed Central

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

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



High-density lipoprotein-associated 17beta-estradiol fatty acyl ester uptake by Fu5AH hepatoma cells: implications of the roles of scavenger receptor class B, type I and the low-density lipoprotein receptor.  


17beta-estradiol (E2) fatty acyl esters naturally incorporate into high-density lipoprotein (HDL). The objective was to elucidate mechanisms involved in HDL-associated E2 cellular uptake and to determine the intracellular distribution of E2 and its fatty acyl esters (E2-FAE) after uptake. [3H]E2 or [3H] cholesterol was incubated with human serum for 24 h to allow for fatty acyl esterification. Total-HDL containing [3H]E2-FAE or [3H]cholesterol esters was isolated by sequential density ultracentrifugation and then incubated with Fu5AH rat hepatoma cells for various time points. Cellular uptake was determined by intracellular radioactivity as a percentage of total radioactivity. Chemical inhibition of scavenger receptor class B, type I and low-density lipoprotein (LDL) receptor competition assays were performed to determine cellular uptake mechanisms. Compared to HDL-[3H]cholesterol, cellular uptake of HDL-[3H]E2 occurred at an initially rapid rate. SR-BI inhibition resulted in a decrease in HDL-E2 uptake and LDL impaired this uptake in a concentration-dependent manner. Accordingly, pretreatment of cells with BLT-1 combined with LDL addition significantly attenuated HDL-E2 uptake. HDL-E2-FAE was hydrolyzed into free E2 with the maximum at 24 h. Fu5AH cells facilitate HDL-E2 uptake by at least SR-BI and LDL receptor pathways and intracellular hydrolysis of E2-FAE into free E2 ensues. PMID:17905649

Badeau, Robert M; Metso, Jari; Tikkanen, Matti J; Jauhiainen, Matti



Beta-blocker induced changes in the cholesterol: High-density lipoprotein cholesterol ratio and risk of coronary heart disease  

Microsoft Academic Search

Summary The lowering of blood pressure with beta-blocking drugs has had a low impact on coronary heart disease (CHD) mortality and the question has been raised whether adverse changes in plasma lipoproteins offset the benefits of blood pressure reduction. Comparison of plasma lipoprotein concentrations in hypertensive patients treated with commonly used beta-blockers with lipoprotein concentrations in patients with coronary heart

B. G. Woodcock; N. Rietbrock



Clinical expression in heterozygotes of two frequent low density lipoprotein receptor gene mutations in the French Canadian population  

SciTech Connect

Five mutations in the low density lipoprotein (LDL) receptor (R) gene account for approximately 83% of cases of heterozygous familial hypercholesterolemia (hFH) in French Canadians in Quebec. The two most prevalent mutations are a >10kb deletion (10kb) of the promoter region resulting in a null allele (60.5% of cases) and a trp{sub 66}{r_arrow}gly missense mutation in exon 3 (ex3) resulting in a binding-defective R (11.7%). We have compared the phenotypic expression of these two mutations in 427 10kb hFH patients, 239 women (age 37.5 {plus_minus} 14.2 years) and 188 men (33.7 {plus_minus} 11.7) and 69 ex3 hFH patients, 42 women (40.6 {plus_minus} 14.3) and 27 men (36.8 {plus_minus}13.2). All data were analyzed separately for women and men. Tendon xanthomas were more prevalent in the 10kb (women 63%, men 68%) than in the ex3 patients (48%,48%). Total and LDL cholesterol were significantly higher in the 10kb patients with than without xanthomas but similar in ex3 patients. There were no significant differences in plasma lipoprotein concentrations between 10kb and ex3 patients with coronary artery disease (CAD) or between 10kb and ex3 patients without CAD. Among men with CAD, those with 10kb were significantly younger than those with ex3 (39.6 {plus_minus} 9.8, n=93 and 46.4 {plus_minus} 7.0, n=9, respectively). In both sexes, high plasma lipoprotein concentrations conferred an increased risk of CAD in 10kb but not in ex3 patients. Thus, as in homozygotes (previous study), the >10kb deletion is associated with more severe expression of FH than is the exon 3 mutation, although the plasma lipoprotein concentrations are not significantly different between the 10kb and ex3 heterozygotes. Since in homozygotes plasma cholesterol levels in 10kb are 60% higher than in ex3 patients, these observations suggest that the expression of the normal LDL-R allele compensates for the lack of a second allele in 10kb heterozygotes.

Roy, M.; Minnich, A.; Davignon, J. [Clinical Research Institute of Montreal, Quebec (Canada)



Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections.  

PubMed Central

Lipoproteins can bind lipopolysaccharide (LPS) and decrease the LPS-stimulated production of pro-inflammatory cytokines. We investigated the effect of increased plasma concentrations of low-density-lipoproteins (LDL) on survival and cytokine production after a lethal challenge with either LPS or live Gram-negative bacteria in LDL receptor deficient mice (LDLR-/-). The LDLR-/- mice challenged with LPS had an eightfold increased LD50 when compared with the wild type controls (C57Bl/6J), while tumor necrosis factor alpha (TNFalpha) and interleukin-1 alpha (IL-1 alpha) plasma concentrations were decreased twofold. LDLR-/- mice had significantly lower and delayed mortality than control mice after infection with Klebsiella pneumoniae. No differences in the outgrowth of bacteria in the organs were present between the two groups, while circulating cytokine concentrations were decreased twofold in LDLR-/- mice. In contrast, the LPS-stimulated in vitro production of cytokines by peritoneal macrophages of LDLR-/- mice was significantly increased compared with controls. This increase was associated with enhanced specific binding of LPS to the macrophages of LDLR-/- mice. In conclusion, endogenous LDL can protect against the lethal effects of endotoxin and Gram-negative infection. At least part of this protection is achieved through decreased in vivo production of pro-inflammatory cytokines, in spite of increased cytokine production capacity. PMID:8617867

Netea, M G; Demacker, P N; Kullberg, B J; Boerman, O C; Verschueren, I; Stalenhoef, A F; van der Meer, J W



An Immunohistochemical Analysis to Validate the Rationale behind the Enhanced Immunogenicity of D-Ribosylated Low Density Lipo-Protein  

PubMed Central

Advanced glycation end products (AGEs) are thought to contribute to the abnormal lipoprotein profiles and increased risk of cardiovascular disease in patients with diabetes and renal failure. D-ribose is one of the naturally occurring pentose monosaccharide present in all living cells and is a key component of numerous biomolecules involved in many important metabolic pathways. Formation of D-ribose derived glycated low density lipoprotein (LDL) has been previously demonstrated but no studies have been performed to assess the immune complex deposition in the kidney of rabbits immunized with glycated LDL. In this study, LDL was glycated with D-ribose, and it was further used as an immunogen for immunizing NZW female rabbits. The results showed that female rabbits immunized with D-ribose modified LDL induced antibodies as detected by direct binding and competitive ELISA. The modified LDL was found to be highly immunogenic eliciting high titer immunogen-specific antibodies, while the native forms were moderately immunogenic. The induced antibodies from modified LDL exhibited wide range of heterogeneity in recognizing various proteins and amino acids conformers. Furthermore, our histopathological results illustrated the deposits of immune complex in glomerular basement membrane in rabbits immunized with D-ribose-LDL. PMID:25393017

Akhter, Firoz; Khan, M. Salman; Singh, Sarika; Ahmad, Saheem



Peroxisome proliferator-activated receptor ? promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage  

PubMed Central

Significant attention has focused on the role of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, recent advances have identified triglyceride-rich lipoproteins [e.g., very LDL (VLDL)] as independent risk predictors for this disease. We have previously demonstrated peroxisome proliferator-activated receptor (PPAR)?, but not PPAR?, is the major nuclear VLDL sensor in the macrophage, which is a crucial component of the atherosclerotic lesion. Here, we show that, in addition to ?-oxidation and energy dissipation, activation of PPAR? by VLDL particles induces key genes involved in carnitine biosynthesis and lipid mobilization mediated by a recently identified TG lipase, transport secretion protein 2 (also named desnutrin, iPLA2?, and adipose triglyceride lipase), resulting in increased fatty acid catabolism. Unexpectedly, deletion of PPAR? results in derepression of target gene expression, a phenotype similar to that of ligand activation, suggesting that unliganded PPAR? suppresses fatty acid utilization through active repression, which is reversed upon ligand binding. This unique transcriptional mechanism assures a tight control of the homeostasis of VLDL-derived fatty acid and provides a therapeutic target for other lipid-related disorders, including dyslipidemia and diabetes, in addition to coronary artery disease. PMID:16467150

Lee, Chih-Hao; Kang, Kihwa; Mehl, Isaac R.; Nofsinger, Russell; Alaynick, William A.; Chong, Ling-Wa; Rosenfeld, John M.; Evans, Ronald M.



Microsomal triglyceride transfer protein activity remains unchanged in rat livers under conditions of altered very-low-density lipoprotein secretion.  

PubMed Central

Microsomal triglyceride transfer protein (MTP) is a heterodimeric protein consisting of a unique 97 kDa subunit and protein disulphide isomerase, that mediates the transfer of lipid between membranes and nascent lipoproteins. Mutations in the gene encoding the 97 kDa subunit of the protein cause the rare autosomal recessive disorder abetalipoproteinaemia. Recent findings in cultured cells indicate that the 5' promoter region contains an insulin-responsive element, suggesting that the gene is responsive to insulin regulation. In this study we examined two cases where very-low-density lipoprotein (VLDL) secretion is markedly reduced: the streptozotocin-diabetic rat and 10-day-old suckling rats. In both cases MTP activity was unaltered compared with that in control animals. Equal levels of MTP were also apparent in the livers of all groups of animals, as measured by immunoblotting with an anti-MTP antiserum. These findings indicate that factors other than MTP activity are responsible for the reduction in hepatic VLDL triglyceride secretion observed in the suckling and diabetic animals. Images Figure 2 PMID:7646432

Brett, D J; Pease, R J; Scott, J; Gibbons, G F



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

PubMed Central

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

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



Murine mammary-derived cells secrete the N-terminal 41% of human apolipoprotein B on high density lipoprotein-sized lipoproteins containing a triacylglycerol-rich core.  

PubMed Central

The cDNA encoding the N-terminal 41% of human apolipoprotein B (apoB), apoB-41, was transfected into nonhepatic, nonintestinal, mammary-derived mouse cells (C127) to generate stably transfected cells expressing human apoB-41 (C127B-41). As determined by centrifugation, apoB-41 is secreted exclusively on lipoproteins (LPs) having a peak density of 1.13 g/ml. Electron microscopy of apoB-41-containing LPs purified by immunoaffinity chromatography showed round particles about 12 nm in diameter. No discoidal particles were observed. Characterization of apoB-41-associated lipids after labeling C127B-41 cells with [3H]oleate and immunoprecipitating the secreted LPs with antibodies to apoB showed that 3H-labeled triacylglycerols were a major lipid class and accounted for about 54% of the total labeled lipids. Cholesterol esters and phospholipids accounted for about 6% and 22%, respectively. Incubation of cells with 0.4 mM oleate resulted in an increased incorporation of the added oleate into lipids associated with secreted apoB-41, along with a 2- to 3-fold increased secretion of apoB-41. The newly formed LPs appear to be transported through the Golgi complex, as brefeldin A (1 microgram/ml) and monensin (1 microM) greatly reduced (> 90%) the secretion of labeled apoB-41 and the amount of triacylglycerol and phospholipid associated with it. Microsomal triacylglycerol transfer protein (MTP) was not detected in these cells. Taken together, the data presented demonstrate that apoB-41 can direct the assembly and secretion of LPs that contain a triacylglycerol-rich core in nonhepatic cells that apparently lack MTP. These cells, therefore, represent an important model for studying LP assembly and may offer some advantages over cultured hepatic or intestinal cells that express their endogenous apoB gene. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:7846033

Herscovitz, H; Kritis, A; Talianidis, I; Zanni, E; Zannis, V; Small, D M



Protective effect of magnoflorine isolated from coptidis rhizoma on Cu2+-induced oxidation of human low density lipoprotein.  


The aim of this study was to investigate the antioxidant activity of magnoflorine, an alkaloid isolated from Coptidis Rhizoma, against the oxidation of native low density lipoprotein (LDL) and modified LDL. Magnoflorine was found to inhibit the copper-mediated (Cu2+) oxidation of LDL, as well as of glycated and glycoxidated LDL by increasing the lag time of conjugated diene formation and preventing the generation of thiobarbituric acid reactive substances (TBARS). In addition, the results from the fluorescence emission spectra of tryptophan (Trp) supported that the antioxidant activity of magnoflorine could be associated with the protective effect on the structural modification of apolipoprotein B (apoB) required for LDL oxidation. These results suggest that magnoflorine may be useful for preventing the oxidation of various LDL forms. PMID:17973202

Hung, Tran Manh; Na, MinKyun; Min, Byung Sun; Zhang, Xinfeng; Lee, IkSoo; Ngoc, Tran Minh; Thuong, Phuong Thien; Sok, Dai-Eun; Bae, KiHwan



Effect of nicomol on high density lipoprotein (HDL) subfractions, HDL2e and HDL3e, separated by electrophoresis.  


High density lipoprotein (HDL) fractions were separated by dextran sulfate-Mg++ from sera of 5 healthy males before and after oral administration of a daily 1200 mg dose of Nicomol (2,2,6,6-tetrakis (nicotinoyloxymethyl) cyclohexanol; Cholexamin, Kyorin Pharmaceutical Co. Ltd.) for 2 weeks. The HDL fractions were further subdivided into HDL2e and HDL3e by Utermann's electrophoretic method on polyacrylamide gel containing lauric acid. These subfractions roughly corresponded to HDL2 and HDL3, respectively, which were separated by ultracentrifugation. Nicomol treatment increased the HDL2e/HDL3e ratio as is observed for the HDL2/HDL3 ratio, in addition to the increase in total HDL cholesterol concentration. The electrophoretic determination of HDL2e/HDL3e ratio in combination with HDL cholesterol level seemed to be clinically important in assessment of the alteration of HDL2 and HDL3 under physiological and pathological conditions. PMID:6456646

Ikeda, S; Nagashima, H; Taketa, K; Watanabe, M



Three complementary techniques for the clarification of temperature effect on low-density lipoprotein-chondroitin-6-sulfate interaction.  


A rigorous processing of adsorption data from quartz crystal microbalance technology was successfully combined with the data obtained by partial filling affinity capillary electrophoresis and molecular dynamics for the clarification of the temperature effect on the interaction of a major glycosaminoglycan chain chondroitin-6-sulfate (C6S) of proteoglycans with low-density lipoprotein (LDL) and with a peptide fragment of apolipoprotein B-100 (residues 3359-3377 of LDL, PPBS). Two experimental techniques and computational atomistic methods demonstrated a nonlinear pattern of the affinity of C6S at temperatures above 38.0 °C to both LDL and PPBS. The temperature affects the interaction of C6S with LDL and PPBS by influencing the structural behavior of glycosaminoglycan C6S and/or that of LDL. PMID:24055620

Cilpa-Karhu, Geraldine; Lipponen, Katriina; Samuelsson, Jörgen; Oörni, Katariina; Fornstedt, Torgny; Riekkola, Marja-Liisa



Effect of structure and composition of reconstituted high density lipoproteins on phosphatidylcholine transfer by human plasma phospholipid transfer protein  

SciTech Connect

Discoidal-reconstructed high density lipoproteins (rHDL) were used to study the effect of HDL substrates on phosphatidylcholine (PC) transfer by human plasma phospholipid transfer protein (PLTP) by changing the composition and size of rHDL. Sonicated egg-PC:cholesterol vesicles containing radiolabeled dipalmitoyl-PC ({sup 14}C-DPPC) were used as donors and varied rHDL, consisting of apolipoprotein, phospholipid and cholesterol, were used as acceptors. PLTP, purified about 3,400-fold, was used in the experiments. Activity was measured by the percent {sup 14}C-DPPC transferred from vesicles into rHDL. There was no selectivity in facilitated {sup 14}C-DPPC transfer at 5:1, of HDL; however, apolipoprotein (apo) AI-containing rHDL was more stable than apo AII and apo C-containing rHDL in the incubation system. Therefore, apo AI was used in subsequent experiments.

Williams, M.I.



High Density Lipoprotein Loses its Effect to Stimulate Efflux of Cholesterol from Foam Cells After Oxidative Modification  

NASA Astrophysics Data System (ADS)

In this study, we performed oxidative modification of high density lipoprotein (HDL) in vitro. The amount of lipid peroxide increased when either HDL2 or HDL3 was incubated with phosphate-buffered saline containing 5 ? M CuSO_4 for 24 h at 37circ C, indicating that both fractions of HDL were oxidatively modified. This modification resulted in denaturation of apolipoprotein AI on SDS/PAGE and increased the negative charge on agarose gel electrophoresis. When incubated with macrophage-derived foam cells, native HDL caused a marked efflux of cholesterol from them, leading to a decrease in the amount of cholesteryl ester in the cells. However, oxidized HDL showed a lessened effect on the decrease of cholesteryl ester in foam cells. These data suggest that oxidative modification of HDL may stimulate development of atherosclerosis by limiting efflux of cholesterol from foam cells.

Nagano, Yutaka; Arai, Hidenori; Kita, Toru



Both inherited susceptibility and environmental exposure determine the low-density lipoprotein-subfraction pattern distribution in healthy Dutch families.  

PubMed Central

A lipoprotein profile characterized by a predominance of small, dense, low-density lipoprotein (LDL) particles has been associated with an increased risk of atherosclerosis. To investigate whether genetic factors are involved in determining this heavy LDL subfraction pattern, this study was undertaken with the aim of resolving the effects that major genes, multifactorial heritability, and environmental exposures have on the LDL subfraction pattern. In a random sample of 19 healthy Dutch families including 162 individuals, the distribution of the LDL subfraction pattern was determined by density gradient ultracentrifugation. For each subject a specific LDL subfraction profile was observed, characterized by the relative contribution of the three major LDL subfractions--LDL1 (d = 1.030-1.033 g/ml), LDL2 (d = 1.033-1.040 g/ml), and LDL3 (d = 1.040-1.045 g/ml)--to total LDL. A continuous variable, parameter K, was defined to characterize each individual LDL subfraction pattern. Complex segregation analysis of this quantitative trait, under a model which includes a major locus, polygenes, and both common and random environment, was applied to analyze the distribution of the LDL subfraction pattern in these families. The results indicate that the LDL subfraction pattern, described by parameter K, is controlled by a major autosomal, highly penetrant, recessive allele with a population frequency of .19 and an additional multifactorial inheritance component. The penetrance of the more dense LDL subfraction patterns, characterized by values of K < 0, was dependent on age, gender, and, in women, on oral contraceptive use and postmenopausal status. Furthermore, multiple regression analysis revealed that approximately 60% of the variation in the LDL subfraction pattern could be accounted for by alterations in age, gender, relative body weight, smoking habits, hormonal status in women, and lipid and lipoprotein levels. In conclusion, our results indicate that genetic influences as well as environmental exposure, sex, age and hormonal status in women are important in determining the distribution of the LDL subfraction patterns in this population and that these influences may contribute to the explanation of familial clustering of coronary heart disease. PMID:1463012

de Graaf, J; Swinkels, D W; de Haan, A F; Demacker, P N; Stalenhoef, A F



Both inherited susceptibility and environmental exposure determine the low-density lipoprotein-subfraction pattern distribution in healthy Dutch families  

SciTech Connect

A lipoprotein profile characterized by a predominance of small, dense, low-density lipoprotein (LDL) particles has been associated with an increased risk of atherosclerosis. To investigate whether genetic factors are involved in determining this heavy LDL subfraction pattern, this study was undertaken with the aim of resolving the effects that major genes, multifactorial heritability, and environmental exposures have on the LDL subfraction pattern. In a random sample of 19 healthy Dutch families including 162 individuals, the distribution of the LDL subfraction pattern was determined by density gradient ultracentrifugation. For each subject a specific LDL subfraction profile was observed, characterized by the relative contribution of the three major LDL subfractions - LDL1 (d = 1.030-1.033 g/ml), LDL2 (d = 1.033-1.040 g/ml), and LDL3 (d = 1.040-1.045 g/ml) - to total LDL. A continuous variable, parameter K, was defined to characterize each individual LDL subfraction pattern. Complex segregation analysis of this quantitative trait, under a model which includes a major locus, polygenes, and both common and random environment, was applied to analyze the distribution of the LDL subfraction pattern in these families. The results indicate that the LDL subfraction pattern, described by parameter K, is controlled by a major autosomal, highly penetrant, recessive allele with a population frequency of .19 and an additional multifactorial inheritance component. The results indicate that genetic influences as well as environmental exposure, sex, age and hormonal status in women are important in determining the distribution of the LDL subfraction patterns in this population and that these influences may contribute to the explanation of familial clustering of coronary heart disease. 40 refs., 3 figs., 8 tabs.

Graaf, J. de; Swinkels, D.W.; Haan, A.F.J. de; Demacker, P.N.M.; Stalenhoef, A.F.H. (University Hospital, Nijmegen (Netherlands))



New Automated Assay of Small Dense Low-Density Lipoprotein Cholesterol Identifies Risk of Coronary Heart Disease  

PubMed Central

Objective Coronary heart disease (CHD) is the leading cause of death in the United States, yet assessing risk of its development remains challenging. The present study evaluates a new automated assay of small dense low-density lipoprotein cholesterol content (sdLDL-C) and whether sdLDL-C is a risk factor for CHD compared with LDL-C or small LDL particle concentrations derived from nuclear magnetic resonance spectroscopy. Approach and Results sdLDL-C was measured using a new automated enzymatic method, and small LDL concentrations were obtained by nuclear magnetic resonance in 4387 Multi-Ethnic Study of Atherosclerosis participants. Cox regression analysis estimated hazard ratios for developing CHD for 8.5 years after adjustments for age, race, sex, systolic blood pressure, hypertension medication use, high-density lipoprotein cholesterol, and triglycerides. Elevated sdLDL-C was a risk factor for CHD in normoglycemic individuals. Those in the top sdLDL-C quartile showed higher risk of incident CHD (hazard ratio, 2.41; P=0.0037) compared with those in the bottom quartile and indicated greater CHD risk than the corresponding quartile of LDL-C (hazard ratio, 1.75; P=0.019). The association of sdLDL-C with CHD risk remained significant when LDL-C (<2.57 mmol/L) was included in a multivariate model (hazard ratio, 2.37; P=0.012). Nuclear magnetic resonance–derived small LDL concentrations did not convey a significant risk of CHD. Those with impaired fasting glucose or diabetes mellitus showed higher sdLDL-C and small LDL concentrations but neither was associated with higher CHD risk in these individuals. Conclusions This new automated method for sdLDL-C identifies risk for CHD that would remain undetected using standard lipid measures, but only in normoglycemic, nondiabetic individuals. PMID:24233487

Tsai, Michael Y.; Steffen, Brian T.; Guan, Weihua; McClelland, Robyn L.; Warnick, Russell; McConnell, Joseph; Hoefner, Daniel M.; Remaley, Alan T.



Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers.  


The aim of our study was to evaluate the effect of a standardized formulation of a polyphenolic extract of grapes (Leucoselect-Phytosome [LP]) on low-density lipoprotein (LDL) susceptibility to oxidation in a group of heavy smokers. A randomized, double-blind, crossover study was undertaken in 24 healthy male heavy smokers, aged > or = 50 years. Enrolled subjects were given 2 capsules twice daily for 4 weeks (phase 1). Each capsule contained 75 mg of a grape procyanidin extracts and soy-phosphatidlcholine or placebo consisiting of 75 mg lactose and soy-phosphatidlcholine. A wash out period of 3 weeks was then followed by 4 weeks of the opposite treatment (phase 2). Blood samples were taken at baseline and at the end of each phase and assayed for plasma lipids and LDL susceptibility to oxidation. Compliance was good, and no adverse effects were recorded. Subjects did not show significant modification of total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C) and LDL-C during LP treatment. Among oxidative indices, thiobarbituric acid reactive substances (TBARS) concentration was significantly reduced in subjects taking LP (-14.7% +/- 21.1% v +5.0% +/- 18.1%, P <.01), and the lag phase prolonged (+15.4% +/- 24.4% v -0.1% +/- 16.0%, P <.05) compared with placebo and basal values. The antioxidant potential of grape seed extract polyphenols may prove effective in a model of oxidative stress (smoking); however more investigational data are needed before use in wider clinical settings. PMID:14564675

Vigna, Giovanni B; Costantini, Fabrizio; Aldini, Giancarlo; Carini, Marina; Catapano, Alberico; Schena, Fabio; Tangerini, Arianna; Zanca, Rosanna; Bombardelli, Egidio; Morazzoni, Paolo; Mezzetti, Andrea; Fellin, Renato; Maffei Facino, Roberto



Protective Effects of Let-7a and Let-7b on Oxidized Low-Density Lipoprotein Induced Endothelial Cell Injuries  

PubMed Central

Lectin-like low-density lipoprotein receptor 1 (LOX-1) is a receptor for oxidized low density lipoprotein (oxLDL) in endothelial cells. The activation of LOX-1 by oxLDL stimulates the apoptosis and dysfunction of endothelial cells, and contributes to atherogenesis. However, the regulatory factors for LOX-1 are still unclear. MicroRNAs are small, endogenous, non-coding RNAs that regulate gene expressions at a post-transcriptional level. The let-7 family is the second microRNA been discovered, which plays important roles in cardiovascular diseases. Let-7a and let-7b were predicted to target LOX-1 3?-UTR and be highly expressed in endothelial cells. The present study demonstrated that LOX-1 was a target of let-7a and let-7b. They inhibited the expression of LOX-1 by targeting the positions of 310-316 in LOX-1 3?-UTR. Over-expression of let-7a and let-7b inhibited the oxLDL-induced endothelial cell apoptosis, NO deficiency, ROS over-production, LOX-1 upregulation and endothelial nitric oxide synthase (eNOS) downregulation. Moreover, we found that oxLDL treatment induced p38MAPK phosphorylation, NF-?B nuclear translocation, I?B degradation and PKB dephosphorylation. Let-7a or let-7b over-expression attenuated these alterations significantly. The present study may provide a new insight into the protective properties of let-7a and let-7b in preventing the endothelial dysfunction associated with cardiovascular disease, such as atherosclerosis. PMID:25247304

Bao, Mei-hua; Zhang, Yi-wen; Lou, Xiao-ya; Cheng, Yu; Zhou, Hong-hao



Low-density lipoprotein cholesterol and radiotherapy-induced carotid atherosclerosis in subjects with head and neck cancer  

PubMed Central

Background Radiotherapy (RT) is a risk factor for accelerated carotid artery atherosclerotic disease in subjects with head and neck cancer. However, the risk factors of RT-induced carotid artery remodeling are not established. This study aimed to investigate the effects of RT on carotid and popliteal arteries in subjects with head and neck cancer and to evaluate the relationship between baseline clinical and laboratory features and the progression of RT-induced atherosclerosis. Findings Eleven men (age?=?57.9?±?6.2years) with head and neck cancer who underwent cervical bilateral irradiation were prospectively examined by clinical and laboratory analysis and by carotid and popliteal ultrasound before and after treatment (mean interval between the end of RT and the post-RT assessment?=?181?±?47 days). No studied subject used hypocholesterolemic medications. Significant increases in carotid intima-media thickness (IMT) (0.95?±?0.08 vs. 0.87?±?0.05 mm; p?density lipoprotein cholesterol levels showed a direct correlation with RT-induced carotid IMT change (r?=?0.66; p?=?0.027), while no other studied variable exhibited a significant relationship with carotid IMT change. Conclusions These results indicate that RT-induced atherosclerosis is limited to the irradiated area and also suggest that it may be predicted by low-density lipoprotein cholesterol levels in subjects with head and neck cancer. PMID:24919963



Absence of clinical relationship between oxidized low density lipoproteins and diabetic peripheral neuropathy: a case control study  

PubMed Central

Background The pathophysiology of diabetic peripheral neuropathy (DPN) is complex and uncertain. A potential comorbidity in diabetes mellitus (DM) that may contribute to greater severity of DPN is a lipid disorder, such as with elevated cholesterol, low density lipoproteins or triglycerides. Oxidized low density lipoprotein (oxLDL) is a form of cholesterol that exerts direct toxic effects and contributes to pathogenicity through ligating a receptor called lectin-like receptor (LOX-1). Methods We examined plasma oxLDL levels in cohorts of patients with DPN with neuropathic pain (NeP), DPN patients without NeP, DM patients without DPN, patients with idiopathic peripheral neuropathy, and control subjects without DM or neuropathy. Our outcome measure was extent of oxLDL elevation, measured as fasting with Enzyme-Linked ImmunoSorbant Assay (ELISA) studies. Severity of diabetes was assessed using hemoglobin A1C measurements. Neuropathic severity was measured with the Utah Early Neuropathy Score (UENS). We hypothesized that DPN presence would be associated with oxLDL elevations. Results A total of 115 subjects (47 with DPN and NeP, 23 with DPN without NeP, 12 with diabetes only, 13 with idiopathic peripheral neuropathy, and 20 control subjects without diabetes or neuropathy) were studied. Duration of diabetes and diabetic glycemic measures were similar between populations with DM. Severity of DPN was similar between cohorts with DPN and NeP and DPN without NeP. Plasma oxLDL levels were similar between all cohorts, without any elevation in the presence of DM noted in any cohort with DM. Conclusions oxLDL levels are not different in patients with DPN, and their lack of greater presence suggests that any pathogenic role in human DPN is likely limited. PMID:24520839



High Density and Beta-Lipoprotein Screening for Risk of Coronary Artery Disease in the Context of New Findings on Reverse Cholesterol Transport  

Microsoft Academic Search

This article considers how high density lipoproteins (HDL) act as anti-arteriosclerotic agents, examines the usefulness of HDL indexes alone and in conjunction with other markers of coronary artery disease (CAD), and discusses how HDL markers compare with what one might expect from known metabolic mechanisms. This is accomplished by: (i) an overview of mechanisms associated with CAD, especially new findings

Stanley S. Levinson



Colocalization of 15Lipoxygenase mRNA and Protein with Epitopes of Oxidized Low Density Lipoprotein in Macrophage-Rich Areas of Atherosclerotic Lesions  

Microsoft Academic Search

Oxidation of low density lipoprotein (LDL) enhances its atherogenicity, and inhibition of such oxidation decreases the rate of progression of atherosclerotic lesions. The mechanism of LDL oxidation in vivo remains uncertain, but in vitro studies have suggested that cellular lipoxygenases may play a role by initiating lipid peroxidation in LDL. In situ hybridization studies using a 15-lipoxygenase riboprobe and immunostaining

Seppo Yla-Herttuala; Michael E. Rosenfeld; Sampath Parthasarathy; Christopher K. Glass; Elliott Sigal; Joseph L. Witztum; Daniel Steinberg



Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis  

Microsoft Academic Search

Liver steatosis, which involves accumula- tion of intracytoplasmic lipid droplets, is characteristic of hepatitis C virus (HCV) infection. By use of an in vivo transgenic murine model, we demonstrate that hepatic overexpression of HCV core protein interferes with the hepatic assembly and secretion of triglyceride- rich very low density lipoproteins (VLDL). Core expres- sion led to reduction in microsomal triglyceride




Development of divergent lines of lean and fat broilers using plasma very low density lipoprotein concentration as selection criterion: The first three generations  

Microsoft Academic Search

1. Male and female broilers of a pure line were selected over three generations on the basis of high or low plasma very low density lipoprotein (VLDL) concentration at 7 weeks of age.2. Heritability of plasma VLDL was high (h = 0·50 ± 0·08) and by the third generation mean values in the two lines differed by a factor of

C. C. Whitehead; H. D. Griffin



Clinical significance of High-Density lipoproteins and the development of atherosclerosis: focus on the role of the adenosine triphosphate–Binding cassette protein A1 transporter  

Microsoft Academic Search

Low levels of high-density lipoprotein (HDL) cholesterol constitute a risk factor for coronary artery disease, and there is evidence that increasing HDL cholesterol levels reduces cardiovascular risk. The phenotype of low HDL cholesterol with or without elevated triglycerides is at least as common in patients hospitalized for cardiovascular disease as is hypercholesterolemia, and it is characteristic of diabetes and the

H. Bryan Brewer; Silvia Santamarina-Fojo



Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study  

Microsoft Academic Search

Background Despite the prognostic value of metabolic syndrome for predicting cardiovascular events, few trials have investigated the effects of statin therapy on cardiovascular morbidity and mortality in patients with the metabolic syndrome. Our post hoc analysis of the Treating to New Targets (TNT) study assessed whether intensive lowering of low-density lipoprotein cholesterol with high-dose atorvastatin therapy results in cardiovascular benefits

Prakash Deedwania; Philip Barter; Rafael Carmena; Jean-Charles Fruchart; Scott M Grundy; Steven Haffner; John JP Kastelein; John C LaRosa; Holly Schachner; James Shepherd; David D Waters



A fresh look at an ancient receptor family: Emerging roles for low density lipoprotein receptors in synaptic plasticity and memory formation  

Microsoft Academic Search

The well-known family of low-density lipoprotein receptors represents a collection of ancient membrane receptors that have been remarkably conserved throughout evolution. These multifunctional receptors, known to regulate cholesterol transport, are becoming increasingly interesting to the neuroscience community due to their ability to transduce a diversity of extracellular signals across the membrane in the adult CNS. Their roles in modulating synaptic

Shenfeng Qiu; Kimberly M. Korwek; Edwin J. Weeber



Association of Coronary Atherosclerosis with Hyper Apo Betalipoproteinemia [Increased Protein but Normal Cholesterol Levels in Human Plasma Low Density (beta) Lipoproteins  

Microsoft Academic Search

Most patients with coronary artery disease do not have elevated plasma or low density lipoprotein (LDL) cholesterol. To test whether the protein moiety of LDL, LDL B, might be a parameter to identify ischemic heart disease, the plasma cholesterol, triglyceride, LDL cholesterol, and LDL B were measured in 100 consecutive patients undergoing cardiac catheterization. On the basis of coronary angiography,

Allan Sniderman; Stanley Shapiro; Derek Marpole; Bernard Skinner; Babie Teng; Peter O. Kwiterovich



Simultaneous Production of Superoxide Radical and Singlet Oxygen by Sulphonated Chloroaluminum Phthalocyanine Incorporated in Human Low-density Lipoproteins: Implications for Photodynamic Therapy¶  

Microsoft Academic Search

Sulfonated chloroaluminum phthalocyanines have been studied for their use in the photodynamic therapy (PDT) of tumors. Plasma low-density lipoproteins (LDL) are important carriers of phthalocyanines in the blood, but on exposure to visible light, phthalocyanine-loaded LDL undergo an oxida- tion process that propagates to erythrocytes. We attempted to identify the reactive species involved in LDL and erythrocyte oxidation by means

Joana Martins; Leonor Almeida; João Laranjinha



Effect of liver X receptor activation on the very low density lipoprotein secretion and messenger ribonucleic acid level of related genes in goose primary hepatocytes.  


In this study, we investigated the role of liver X receptor (LXR) activation in hepatic assembly and in the secretion of very low density lipoprotein-triglycerides in goose primary hepatocytes. Goose primary hepatocytes were isolated and treated with the LXR agonist T0901317. Total triglyceride accumulation, intracellular and extracellular triglyceride concentrations, extracellular very low density lipoprotein concentration, and gene expression levels of LXR?, microsomal triglyceride transfer protein, acyl coenzyme A:diacylglycerol acyltransferase (DGAT) 1, and DGAT2 were measured in primary hepatocytes. We found a dose-dependent upregulation of total and intracellular TG accumulation when using 0, 0.01, 0.1, 1, and 10 ?M T0901317, but the extracellular triglyceride and very low density lipoprotein concentrations were dose dependent only when the T0901317 concentration was below 1 ?M; as compared with 1 ?M T0901317, 10 ?M T0901317 had an inhibiting effect (P < 0.05). The mRNA levels of all the detected genes increased in the presence of T0901317. The change in LXR? and DGAT1 was dose dependent, and the mRNA levels of microsomal triglyceride transfer protein and DGAT2 increased with a T0901317 concentration up to 1 ?M, but decreased when treated with 10 ?M T0901317 (P < 0.05). In conclusion, the secretion of very low density lipoprotein plays a role in pharmacologically activating the LXR-induced development of hepatocellular steatosis in geese. PMID:21248338

Han, C C; Wang, J W; Pan, Z X; Tang, H; Xiang, S X; Wang, J; Li, L; Xu, F; Wei, S H



A Low Prevalence of Coronary Heart Disease among Subjects with Increased High-Density Lipoprotein Cholesterol Levels, Including Those with Plasma Cholesteryl Ester Transfer Protein Deficiency  

Microsoft Academic Search

Background.Use of genetic analysis may improve the predictive value of risk factors for disease. A high plasma level of high-density lipoprotein (HDL) cholesterol is a strong negative risk factor for coronary heart disease (CHD). Cholesteryl ester transfer protein (CETP) deficiency causes increased levels of HDL cholesterol. However, recent studies suggest that CETP deficiency is a risk factor for CHD despite

Yuri Moriyama; Tomonori Okamura; Akihiro Inazu; Mitsunori Doi; Hiroyasu Iso; Yoshitaka Mouri; Yoshinori Ishikawa; Hideyoshi Suzuki; Minoru Iida; Junji Koizumi; Hiroshi Mabuchi; Yoshio Komachi



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

ERIC Educational Resources Information Center

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

Lungo, Diane; And Others


Molina et al., LDLR and HCV infection of normal hepatocyte 1 The Low Density Lipoprotein Receptor plays a role in the  

E-print Network

Molina et al., LDLR and HCV infection of normal hepatocyte 1 The Low Density Lipoprotein Receptor plays a role in the infection of primary human hepatocytes by hepatitis C virus Sonia Molina1 *, Valérie title : LDLR and HCV infection of normal hepatocyte Corresponding author: Patrick Maurel, Inserm U632

Paris-Sud XI, Université de


Human absorption of a supplement containing purified hydroxytyrosol, a natural antioxidant from olive oil, and evidence for its transient association with low-density lipoproteins  

Microsoft Academic Search

There is growing interest in the health effects of olive oil polyphenols, particularly hydroxytyrosol (HT), for their potential application in the treatment of inflammatory conditions such as cardiovascular disease (CVD). As oxidative modification of low-density lipoproteins (LDL) plays a central role in the development of CVD, natural antioxidants are a main target for the nutraceutical industry. In this study we

Maria González-Santiago; Juristo Fonollá; Eduardo Lopez-Huertas



Low density lipoprotein receptor-related protein 1 expression correlates with cholesteryl ester accumulation in the myocardium of ischemic cardiomyopathy patients  

PubMed Central

Our hypothesis was that overexpression of certain lipoprotein receptors might be related to lipid accumulation in the human ischemic myocardium. Intramyocardial lipid overload contributes to contractile dysfunction and arrhythmias in cardiomyopathy. Thus, the purpose of this study was to assess the effect of hypercholesterolemic LDL and hypertrigliceridemic VLDL dose on LRP1 expression in cardiomyocytes, as well as the potential correlation between LRP1 expression and neutral lipid accumulation in the left ventricle tissue from ischemic cardiomyopathy patients. Cell culture experiments include control and LRP1-deficient cardiomyocytes exposed to lipoproteins under normoxic and hypoxic conditions. Explanted hearts from 18 ICM patients and eight non-diseased hearts (CNT) were included. Low density lipoprotein receptor-related protein 1 (LRP1), very low density lipoprotein receptor (VLDLR) and low density lipoprotein receptor (LDLR) expression was analyzed by real time PCR and Western blotting. Cholesteryl ester (CE), triglyceride (TG) and free cholesterol (FC) content was assess by thin layer chromatography following lipid extraction. Western blotting experiments showed that protein levels of LRP1, VLDLR and HIF-1? were significantly upregulated in ischemic hearts. Immunohistochemistry and confocal microscopy analysis showed that LRP1 and HIF-1? were upregulated in cardiomyocytes of ICM patients. In vitro studies showed that VLDL, LDL and hypoxia exerted an upregulatory effect on LRP1 expression and that LRP1 played a major role in cholesteryl ester accumulation from lipoproteins in cardiomyocytes. Myocardial CE accumulation strongly correlated with LRP1 levels in ischemic hearts. Taken together, our results suggest that LRP1 upregulation is key for myocardial cholesterol ester accumulation in ischemic human hearts and that LRP1 may be a target to prevent the deleterious effects of myocardial cholesterol accumulation in ischemic cardiomyopathy. PMID:22873206