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The Value and Distribution of High-Density Lipoprotein Subclass in Patients with Acute Coronary Syndrome  

PubMed Central

Background High-density lipoprotein (HDL) enhances cholesterol efflux from the arterial wall and exhibits potent anti-inflammatory and anti-atherosclerosis (AS) properties. Whether raised HDL levels will clinically benefit patients with acute coronary syndrome (ACS) and the value at which these effects will be apparent, however, is debatable. This study examined the HDL subclass distribution profile in patients with ACS. Methods Plasma HDL subclasses were measured in 158 patients with established ACS and quantified by two-dimensional gel electrophoresis and immunoblotting. ACS diagnosis was based on symptoms of cardiac ischemia, electrocardiogram (ECG) abnormalities, speciality cardiac enzyme change along with presence of coronary heart disease (CHD) on coronary angiography. Results The small-sized pre?1-HDL, HDL3b, and HDL3a levels were significantly higher, and the large-sized HDL2a and HDL2b levels were significantly lower in patients with ACS than in those with stable angina pectoris (SAP) and in normal control subjects. Meanwhile, with an elevation in the low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), body mass index (BMI), and blood pressure (BP), and the reduction in the high density lipoprotein cholesterol (HDL-C) levels, the HDL2b contents significantly decreased and the pre?1-HDL contents significantly increased in patients with ACS. The correlation analysis revealed that the apolipoprotein (apo)A-I levels were positively and significantly with all HDL subclasses contents; plasma total cholesterol (TC) and fasting plasma glucose (FPG) levels were inversely associated with HDL2a, and HDL2b. Moreover, the FPG levels were positively related to HDL3c, HDL3b, and HDL3a in ACS patients. Conclusion The HDL subclass distribution profile remodeling was noted in the patients with ACS. Plasma lipoprotein and FPG levels, BP, and BMI play an important role in the HDL subclass metabolism disorder for patients with ACS. The HDL subclass distribution phenotype might be useful as a novel biomarker to assist in the risk stratification of patients with ACS. PMID:24465490

Tian, Li; Li, Chuanwei; Liu, Yinghui; Chen, Yucheng; Fu, Mingde



The Interplay between Size, Morphology, Stability, and Functionality of High-Density Lipoprotein Subclasses  

PubMed Central

High-density lipoprotein (HDL) mediates reverse cholesterol transport (RCT), wherein excess cholesterol is conveyed from peripheral tissues to the liver and steroidogenic organs. During this process HDL continually transitions between subclass sizes, each with unique biological activities. For instance, RCT is initiated by the interaction of lipid-free/lipid-poor apolipoprotein A-I (apoA-I) with ABCA1, a membrane-associated lipid transporter, to form nascent HDL. Because nearly all circulating apoA-I is lipid-bound, the source of lipid-free/lipid-poor apoA-I is unclear. Lecithin:cholesterol acyltransferase (LCAT) then drives the conversion of nascent HDL to spherical HDL by catalyzing cholesterol esterification, an essential step in RCT. To investigate the relationship between HDL particle size and events critical to RCT such as LCAT activation and lipid-free apoA-I production for ABCA1 interaction, we reconstituted five subclasses of HDL particles (rHDL of 7.8, 8.4, 9.6, 12.2, and 17.0 nm in diameter, respectively) using various molar ratios of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, free cholesterol, and apoA-I. Kinetic analyses of this comprehensive array of rHDL particles suggest that apoA-I stoichiometry in rHDL is a critical factor governing LCAT activation. Electron microscopy revealed specific morphological differences in the HDL subclasses that may affect functionality. Furthermore, stability measurements demonstrated that the previously uncharacterized 8.4 nm rHDL particles rapidly convert to 7.8 nm particles, concomitant with the dissociation of lipid-free/lipid-poor apoA-I. Thus, lipid-free/lipid-poor apoA-I generated by the remodeling of HDL may be an essential intermediate in RCT and HDL’s in vivo maturation. PMID:18366184

Cavigiolio, Giorgio; Shao, Baohai; Geier, Ethan G.; Ren, Gang; Heinecke, Jay W.; Oda, Michael N.



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



Low density lipoprotein subclasses and response to a low-fat diet in healthy men  

SciTech Connect

Lipid and lipoprotein response to reduced dietary fat intake was investigated in relation to differences in distribution of LDL subclasses among 105 healthy men consuming high-fat (46%) and low-fat (24%) diets in random order for six weeks each. On high-fat, 87 subjects had predominantly large, buoyant LDL as measured by gradient gel electrophoresis and confirmed by analytic ultracentrifugation (pattern A), while the remainder had primarily smaller, denser LDL (pattern B). On low-fat, 36 men changed from pattern A to B. Compared with the 51 men in the stable A group, men in the stable B group (n = 18) had a three-fold greater reduction in LDL cholesterol and significantly greater reductions in plasma apoB and mass of intermediate (LDL II) and small (LDL III) LDL subtractions measured by analytic ultracentrifugation. In both stable A and change groups, reductions in LDL-cholesterol were not accompanied by reduced plasma apoB, consistent with the observation of a shift in LDL particle mass from larger, lipid-enriched (LDL I and II) to smaller, lipid-depleted (LDL III and IV) subfractions, without significant change in particle number. Genetic and environmental factors influencing LDL subclass distributions thus may also contribute substantially to interindividual variation in response to a low-fat diet.

Krauss, R.M.; Dreon, D.M. [Lawrence Berkeley Lab., CA (United States). Life Sciences Div.



Lipoprotein subclass metabolism in nonalcoholic steatohepatitis.  


Nonalcoholic steatohepatitis (NASH) is associated with increased synthesis of triglycerides and cholesterol coupled with increased VLDL synthesis in the liver. In addition, increased cholesterol content in the liver associates with NASH. Here we study the association of lipoprotein subclass metabolism with NASH. To this aim, liver biopsies from 116 morbidly obese individuals [age 47.3 ± 8.7 (mean ± SD) years, BMI 45.1 ± 6.1 kg/m(2), 39 men and 77 women] were used for histological assessment. Proton NMR spectroscopy was used to measure lipid concentrations of 14 lipoprotein subclasses in native serum samples at baseline and after obesity surgery. We observed that total lipid concentration of VLDL and LDL subclasses, but not HDL subclasses, associated with NASH [false discovery rate (FDR) < 0.1]. More specifically, total lipid and cholesterol concentration of VLDL and LDL subclasses associated with inflammation, fibrosis, and cell injury (FDR < 0.1), independent of steatosis. Cholesterol concentration of all VLDL subclasses also correlated with total and free cholesterol content in the liver. All NASH-related changes in lipoprotein subclasses were reversed by obesity surgery. High total lipid and cholesterol concentration of serum VLDL and LDL subclasses are linked to cholesterol accumulation in the liver and to liver cell injury in NASH. PMID:25344588

Männistö, Ville T; Simonen, Marko; Soininen, Pasi; Tiainen, Mika; Kangas, Antti J; Kaminska, Dorota; Venesmaa, Sari; Käkelä, Pirjo; Kärjä, Vesa; Gylling, Helena; Ala-Korpela, Mika; Pihlajamäki, Jussi



Effects of Lipid-Lowering Drugs on High-Density Lipoprotein Subclasses in Healthy Men—A Randomized Trial  

PubMed Central

Context and Objective Investigating the effects of lipid-lowering drugs on HDL subclasses has shown ambiguous results. This study assessed the effects of ezetimibe, simvastatin, and their combination on HDL subclass distribution. Design and Participants A single-center randomized parallel 3-group open-label study was performed in 72 healthy men free of cardiovascular disease with a baseline LDL-cholesterol of 111±30 mg/dl (2.9±0.8 mmol/l) and a baseline HDL-cholesterol of 64±15 mg/dl (1.7±0.4 mmol/l). They were treated with ezetimibe (10 mg/day, n?=?24), simvastatin (40 mg/day, n?=?24) or their combination (n?=?24) for 14 days. Blood was drawn before and after the treatment period. HDL subclasses were determined using polyacrylamide gel-tube electrophoresis. Multivariate regression models were used to determine the influence of treatment and covariates on changes in HDL subclass composition. Results Baseline HDL subclasses consisted of 33±10% large, 48±6% intermediate and 19±8% small HDL. After adjusting for baseline HDL subclass distribution, body mass index, LDL-C and the ratio triglycerides/HDL-C, there was a significant increase in large HDL by about 3.9 percentage points (P<0.05) and a decrease in intermediate HDL by about 3.5 percentage points (P<0.01) in both simvastatin-containing treatment arms in comparison to ezetimibe. The parameters obtained after additional adjustment for the decrease in LDL-C indicated that about one third to one half of these effects could be explained by the extent of LDL-C-lowering. Conclusions In healthy men, treatment with simvastatin leads to favorable effects on HDL subclass composition, which was not be observed with ezetimibe. Part of these differential effects may be due to the stronger LDL-C-lowering effects of simvastatin. Trial Registration NCT00317993 PMID:24662777

Spenrath, Nadine; Montalto, Giuseppe; Krone, Wilhelm; Gouni-Berthold, Ioanna



Sleep Apnea Is Related to the Atherogenic Phenotype, Lipoprotein Subclass B  

PubMed Central

Study Objectives: Sleep apnea has been implicated as an independent risk factor for atherosclerotic coronary artery disease (CAD). An association between the severity of sleep apnea and total cholesterol levels has previously been reported. However, the association with small dense low density lipoprotein (LDL) cholesterol concentration (subclass B), one of the strongest predictors of atherosclerosis, is unknown. We examined the relationship between sleep apnea and LDL subclass B, considering body size. Methods: This is a cross-sectional observational cohort of participants enrolled in a cardiovascular health study. Sleep apnea was assessed with a validated portable monitor. Lipid panels included total cholesterol, triglycerides, high density lipoprotein cholesterol, LDL cholesterol, and LDL subclasses A, B, and A/B. Sleep apnea was analyzed categorically using the apnea hypopnea index (AHI). Results: A total of 519 participants were evaluated. Mean age was 58.7 ± 7.4 years; BMI was 29.6 ± 5.7; 65% were female; 59% were Caucasian, and 37% were African American. Among participants with abnormal waist circumference by ATP III criteria, moderate to severe sleep apnea (AHI ? 25) was not independently associated with LDL subclass B. In contrast, among participants with normal waist circumference, moderate to severe sleep apnea was associated with 4.5-fold odds of having LDL subclass B. Conclusions: Sleep apnea is independently associated with an atherogenic phenotype (LDL subclass B) in non-obese individuals. The association between sleep apnea and LDL subclass B in those with normal waist circumference may account, in part, for the increased risk of atherosclerosis and subsequent vascular events. Citation: Luyster FS; Kip KE; Drumheller OJ; Rice TB; Edmundowicz D; Matthews K; Reis SE; Strollo PJ. Sleep apnea is related to the atherogenic phenotype, lipoprotein subclass B. J Clin Sleep Med 2012;8(2):155-161. PMID:22505860

Luyster, Faith S.; Kip, Kevin E.; Drumheller, Oliver J.; Rice, Thomas B.; Edmundowicz, Daniel; Matthews, Karen; Reis, Steven E.; Strollo, Patrick J.



Fluorometric sedimentation equilibrium for lipoprotein sub-class analysis.  

E-print Network

Fluorometric density gradient ultracentrifugation is used to measure the lipoprotein density profile for cardiovascular disease risk assessment. The work presented establishes the effectiveness of using a single-spin separation as both an analytical...

Henriquez, Ronald Rene



Lipoprotein subclass profiles in young adults born preterm at very low birth weight  

PubMed Central

Background Adults born preterm at very low birth weight (VLBW???1500g) have increased risk factors for cardiovascular diseases including high blood pressure and impaired glucose regulation. Non-optimal lipoprotein profile is generally also likely to affect the increased cardiovascular risk, but lipoprotein subclass level data on adults born at VLBW are sparse. Subjects and methods We studied 162 subjects born at VLBW and 169 term-born controls, aged 19 to 27?years. Total lipid, triglyceride and cholesterol concentrations of 14 lipoprotein subclasses were determined by proton nuclear magnetic resonance spectroscopy in the fasting state and in 2-hour serum samples from an oral glucose tolerance test. Findings In comparison to controls, VLBW subjects had significantly higher fasting concentration of triglycerides in chylomicrons and largest very-low-density lipoprotein particles [XXL-VLDL-TG, difference 0.026 (95% CI: 0.004 to 0.049), P?=?0.024], and of triglycerides in small high-density lipoprotein particles [S-HDL-TG, 0.026 (95% CI: 0.002 to 0.051), P?=?0.037]. The seemingly important role of triglycerides was further supported by principal component analysis in which the first component was characterized by multiple lipoprotein triglyceride measures. Conclusions Young adults born at VLBW and their peers born at term had triglyceride-related differences in both VLDL and HDL subclasses. These differences suggest that the increased risk factors for cardiovascular diseases among the VLBW individuals in adulthood may partly relate to impaired triglyceride metabolism. PMID:23631373



Linkage of atherogenic lipoprotein phenotype to the low density lipoprotein receptor locus on the short arm of chromosome 19  

Microsoft Academic Search

The atherogenic lipoprotein phenotype (ALP) is a common heritable trait characterized by a predominance of small, dense low density lipoprotein (LDL) particles (subclass pattern B), increased levels of triglyceride-rich lipoproteins, reductions in high density lipoprotein, and a 3-fold increased risk of myocardial infarction. Significant two-point linkage was found between ALP and the LDL receptor locus on the short arm of

P. M. Nishina; J P Johnson; J K Naggert; R M Krauss



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))



Very low density lipoproteins provide a vector for secretion of paraoxonase-1 from cells  

Microsoft Academic Search

Paraoxonase-1 (PON1) requires a suitable acceptor complex for its secretion from producing cells. The serum lipoprotein, high-density lipoprotein (HDL) has been shown to accomplish this function, whereas low-density lipoproteins are ineffective. The present study examined the influence of the third serum lipoprotein subclass, very low density lipoproteins (VLDL), on PON1 secretion. VLDL were shown to promote secretion of PON1 from

Sara Deakin; Xenia Moren; Richard W. James



Apolipoprotein B–Containing Lipoprotein Subclasses as Risk Factors for Cardiovascular Disease in Patients With Rheumatoid Arthritis  

PubMed Central

Objective The purpose of this study was to explore whether nontraditional risk factors, such as apolipoprotein C-III (Apo C-III) and its corresponding Apo B lipoprotein (Lp) subclasses, contribute to the risk of cardiovascular disease in rheumatoid arthritis (RA) patients. Methods Apolipoprotein and lipoproteins were measured in 152 RA patients by immunoturbidimetric procedures, electroimmunoassay, and immunoprecipitation. Patients had a coronary artery calcium (CAC) score assessed at baseline and at year 3. Differences in the CAC scores between baseline and year 3 were calculated and dichotomized at 0, where patients with a difference score >0 were denoted as progressors and the rest were denoted as nonprogressors. Differences between means were tested with a 2-sided independent Student’s t-test with Satterthwaite’s adjustment. Proportion differences were tested with a chi-square test. Multiple logistic regression was performed to assess the relationship between apolipoprotein and lipoprotein levels and the dichotomized CAC score. Results Progressors accounted for almost 60% of the cohort. Progressors had significantly higher levels of triglycerides, very low-density lipoprotein (VLDL) cholesterol, total cholesterol/high-density lipoprotein (HDL), triglycerides/HDL, Apo B, LpA-II:B:C:D:E, LpB:C, Apo B/Apo A-I, Apo C-III, and Apo C-III–heparin precipitate than the nonprogressors. After adjusting for age, sex, statin use (yes/no), and hypertension (yes/no), significant risk factors of progressors were total cholesterol, triglycerides, VLDL cholesterol, LDL cholesterol, Apo B, LpB:C, Apo C-III, and Apo B/Apo A-I. Conclusion Apo C-III–containing Apo B lipoprotein subclasses were found to be significantly elevated in progressors compared to nonprogressors. Many of these same lipoproteins were found to be associated with an increase in CAC scores among progressors. These lipoproteins may be considered new risk factors for progression of atherosclerosis in RA patients. PMID:22337612




Lipoprotein subclass analysis by immunospecific density  

E-print Network

the heart are collectively known as heart disease. [1] Coronary heart disease means that blood flow through the coronary arteries has become impaired. A more general term that includes non-coronary arteries is cardiovascular disease (CVD). The most... plaques. The inner walls of arteries become slowly narrower because of a buildup of these plaques, importantly, rupture of a plaque can occur suddenly and the subsequent formation of a blood clot around the ruptured plaque may...

Lester, Sandy Marie



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



Diabetic Retinopathy and Serum Lipoprotein Subclasses in the DCCT\\/EDIC Cohort  

Microsoft Academic Search

PURPOSE. To determine associations between retinopathy status and detailed serum lipoprotein subclass profiles in the Diabetes Control and Complications Trial\\/Epidemiology of Diabetes In- terventions and Complications Study (DCCT\\/EDIC) cohort. METHODS. Persons with type 1 diabetes (440 women, 548 men) from the DCCT\\/EDIC cohort were studied. Retinopathy was characterized by Early Treatment Diabetic Retinopathy Study (ETDRS) scores, hard exudate scores, and

Timothy J. Lyons; Alicia J. Jenkins; Deyi Zheng; Daniel T. Lackland; Daniel McGee; W. Timothy Garvey; Richard L. Klein



High-density lipoproteins delivering interleukin-15.  


Circulating lipoproteins may offer interesting properties as therapeutic carriers for cytokines and hormones, in terms of both stability and bio-distribution. The fusion of apolipoprotein A-I with interleukin-15 (IL-15) targets the latter to high-density lipoproteins (HDLs). The bioactivity of this chimera can be further enhanced by creating triple fusions with IL-15 receptor ? domain involved in IL-15 trans-presentation. PMID:23734302

Ochoa, Maria C; Melero, Ignacio; Berraondo, Pedro



Low-Density Lipoprotein Apheresis  

PubMed Central

Executive Summary Objective To assess the effectiveness and safety of low-density lipoprotein (LDL) apheresis performed with the heparin-induced extracorporeal LDL precipitation (HELP) system for the treatment of patients with refractory homozygous (HMZ) and heterozygous (HTZ) familial hypercholesterolemia (FH). Background on Familial Hypercholesterolemia Familial hypercholesterolemia is a genetic autosomal dominant disorder that is caused by several mutations in the LDL-receptor gene. The reduced number or absence of functional LDL receptors results in impaired hepatic clearance of circulating low-density lipoprotein cholesterol (LDL-C) particles, which results in extremely high levels of LDL-C in the bloodstream. Familial hypercholesterolemia is characterized by excess LDL-C deposits in tendons and arterial walls, early onset of atherosclerotic disease, and premature cardiac death. Familial hypercholesterolemia occurs in both HTZ and HMZ forms. Heterozygous FH is one of the most common monogenic metabolic disorders in the general population, occurring in approximately 1 in 500 individuals1. Nevertheless, HTZ FH is largely undiagnosed and an accurate diagnosis occurs in only about 15% of affected patients in Canada. Thus, it is estimated that there are approximately 3,800 diagnosed and 21,680 undiagnosed cases of HTZ FH in Ontario. In HTZ FH patients, half of the LDL receptors do not work properly or are absent, resulting in plasma LDL-C levels 2- to 3-fold higher than normal (range 7-15mmol/L or 300-500mg/dL). Most HTZ FH patients are not diagnosed until middle age when either they or one of their siblings present with symptomatic coronary artery disease (CAD). Without lipid-lowering treatment, 50% of males die before the age of 50 and 25% of females die before the age of 60, from myocardial infarction or sudden death. In contrast to the HTZ form, HMZ FH is rare (occurring in 1 case per million persons) and more severe, with a 6- to 8-fold elevation in plasma LDL-C levels (range 15-25mmol/L or 500-1000mg/dL). Homozygous FH patients are typically diagnosed in infancy, usually due to the presence of cholesterol deposits in the skin and tendons. The main complication of HMZ FH is supravalvular aortic stenosis, which is caused by cholesterol deposits on the aortic valve and in the ascending aorta. The average life expectancy of affected individuals is 23 to 25 years. In Ontario, it is estimated that there are 13 to 15 cases of HMZ FH. An Ontario clinical expert confirmed that 9 HMZ FH patients have been identified to date. Diagnosis There are 2 accepted clinical diagnostic criterion for the diagnosis of FH: the Simon Broome FH Register criteria from the United Kingdom and the Dutch Lipid Network criteria from the Netherlands. The criterion supplement cholesterol levels with clinical history, physical signs and family history. DNA-based-mutation-screening methods permit a definitive diagnosis of HTZ FH to be made. However, given that there are over 1000 identified mutations in the LDL receptor gene and that the detection rates of current techniques are low, genetic testing becomes problematic in countries with high genetic heterogeneity, such as Canada. Treatment The primary aim of treatment in both HTZ and HMZ FH is to reduce plasma LDL-C levels in order to reduce the risk of developing atherosclerosis and CAD. The first line of treatment is dietary intervention, however it alone is rarely sufficient for the treatment of FH patients. Patients are frequently treated with lipid-lowering drugs such as resins, fibrates, niacin, statins and cholesterol absorption-inhibiting drugs (ezetimibe). Most HTZ FH patients require a combination of drugs to achieve or approach target cholesterol levels. A small number of HTZ FH patients are refractory to treatment or intolerant to lipid-lowering medication. According to clinical experts, the prevalence of refractory HTZ FH in Ontario is between 1 to 5%. Using the mean of 3%, it is estimated that there are approximately 765 refractory HTZ FH patients in Ontario, of which 115 are diagnosed



Serum Amyloid P Component Associates with High Density Lipoprotein as well as Very Low Density Lipoprotein but Not with Low Density Lipoprotein  

Microsoft Academic Search

Serum amyloid P component (SAP) is a glycoprotein in human plasma. We previously showed that SAP is specifically localized in human atherosclerotic lesions, suggesting that SAP may play a role in atherogenesis. In this study, the interactions between human SAP and high density lipoprotein (HDL), low density lipoprotein (LDL) and very low density lipoprotein (VLDL) were investigated by using a

Xiang-An Li; Chikao Yutani; Kentaro Shimokado



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


Low-density lipoprotein particle size, central obesity, cardiovascular fitness, and insulin resistance syndrome markers in obese youths  

Microsoft Academic Search

OBJECTIVE: (1) To determine the prevalence of small dense low-density lipoprotein (SDLDL) particles in obese youths and (2) to compare youths with SDLDL and large buoyant LDL (LBLDL) subclass phenotypes in total body and abdominal fatness, cardiovascular (CV) fitness, and markers of the insulin resistance syndrome (IRS).DESIGN: For group comparisons, subjects were dichotomized into either SDLDL phenotype group or LBDL

H-S Kang; B Gutin; P Barbeau; Litaker; J Allison; N-A Le



Oxidized low-density lipoprotein and atherosclerosis  

Microsoft Academic Search

Atherosclerosis is the leading cause of morbidity and mortality in western society. The most important risk factors for atherosclerosis\\u000a include smoking, hypertension, dyslipidemia, diabetes and a family history of premature atherosclerosis. Several studies indicate\\u000a that an increased plasma low density lipoprotein (LDL) cholesterol constitutes a major risk factor for atherosclerosis. Many\\u000a data support a proatherogenic role for oxidized LDL and

S. Devaraj; I. Jialal



Double Superhelix Model of High Density Lipoprotein*  

PubMed Central

High density lipoprotein (HDL), the carrier of so-called “good” cholesterol, serves as the major athero-protective lipoprotein and has emerged as a key therapeutic target for cardiovascular disease. We applied small angle neutron scattering (SANS) with contrast variation and selective isotopic deuteration to the study of nascent HDL to obtain the low resolution structure in solution of the overall time-averaged conformation of apolipoprotein AI (apoA-I) versus the lipid (acyl chain) core of the particle. Remarkably, apoA-I is observed to possess an open helical shape that wraps around a central ellipsoidal lipid phase. Using the low resolution SANS shapes of the protein and lipid core as scaffolding, an all-atom computational model for the protein and lipid components of nascent HDL was developed by integrating complementary structural data from hydrogen/deuterium exchange mass spectrometry and previously published constraints from multiple biophysical techniques. Both SANS data and the new computational model, the double superhelix model, suggest an unexpected structural arrangement of protein and lipids of nascent HDL, an anti-parallel double superhelix wrapped around an ellipsoidal lipid phase. The protein and lipid organization in nascent HDL envisages a potential generalized mechanism for lipoprotein biogenesis and remodeling, biological processes critical to sterol and lipid transport, organismal energy metabolism, and innate immunity. PMID:19812036

Wu, Zhiping; Gogonea, Valentin; Lee, Xavier; Wagner, Matthew A.; Li, Xin-Min; Huang, Ying; Undurti, Arundhati; May, Roland P.; Haertlein, Michael; Moulin, Martine; Gutsche, Irina; Zaccai, Giuseppe; DiDonato, Joseph A.; Hazen, Stanley L.



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



Maturation of high-density lipoproteins  

PubMed Central

Human high-density lipoproteins (HDLs) are involved in the transport of cholesterol. The mechanism by which HDL assembles and functions is not well understood owing to a lack of structural information on circulating spherical HDL. Here, we report a series of molecular dynamics simulations that describe the maturation of discoidal HDL into spherical HDL upon incorporation of cholesterol ester as well as the resulting atomic level structure of a mature circulating spherical HDL particle. Sixty cholesterol ester molecules were added in a stepwise fashion to a discoidal HDL particle containing two apolipoproteins wrapped around a 160 dipalmitoylphosphatidylcholine lipid bilayer. The resulting matured particle, captured in a coarse-grained description, was then described in a consistent all-atom representation and analysed in chemical detail. The simulations show that maturation results from the formation of a highly dynamic hydrophobic core comprised of cholesterol ester surrounded by phospholipid and protein; the two apolipoprotein strands remain in a belt-like conformation as seen in the discoidal HDL particle, but with flexible N- and C-terminal helices and a central region stabilized by salt bridges. In the otherwise flexible lipoproteins, a less mobile central region provides an ideal location to bind lecithin cholesterol acyltransferase, the key enzyme that converts cholesterol to cholesterol ester during HDL maturation. PMID:19570799

Shih, Amy Y.; Sligar, Stephen G.; Schulten, Klaus



Triglycerides, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol in rats exposed to premium motor spirit fumes  

PubMed Central

Background: Deliberate and regular exposure to premium motor spirit fumes is common and could be a risk factor for liver disease in those who are occupationally exposed. A possible association between premium motor spirit fumes and plasma levels of triglyceride, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol using a rodent model could provide new insights in the pathology of diseases where cellular dysfunction is an established risk factor. Aim: The aim of this study was to evaluate the possible effect of premium motor spirit fumes on lipids and lipoproteins in workers occupationally exposed to premium motor spirit fumes using rodent model. Materials and Methods: Twenty-five Wister albino rats (of both sexes) were used for this study between the 4th of August and 7th of September, 2010. The rats were divided into five groups of five rats each. Group 1 rats were not exposed to premium motor spirit fumes (control group), group 2 rats were exposed for 1 hour daily, group 3 for 3 hours daily, group 4 for 5 hours daily and group 5 for 7 hours daily. The experiment lasted for a period of 4 weeks. Blood samples obtained from all the groups after 4 weeks of exposure were used for the estimation of plasma levels of triglyceride, total cholesterol, high density lipoprotein- cholesterol and low density lipoprotein- cholesterol. Result: Results showed significant increase in means of plasma total cholesterol and low density lipoprotein levels (P<0.05). The mean triglyceride and total body weight were significantly lower (P<0.05) in the exposed group when compared with the unexposed. The plasma level of high density lipoprotein, the ratio of low density lipoprotein to high density lipoprotein and the ratio of total cholesterol to high density lipoprotein did not differ significantly in exposed subjects when compared with the control group. Conclusion: These results showed that frequent exposure to petrol fumes may be highly deleterious to the liver cells. PMID:22540098

Aberare, Ogbevire L.; Okuonghae, Patrick; Mukoro, Nathaniel; Dirisu, John O.; Osazuwa, Favour; Odigie, Elvis; Omoregie, Richard



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


Lipoprotein lipase enhances the interaction of low density lipoproteins with artery-derived extracellular matrix proteoglycans.  


The association of plasma low density lipoproteins (LDL) with arterial proteoglycans (PG) is of key importance in LDL retention and modification in the artery wall. Lipoprotein lipase (LpL), the rate-limiting enzyme for hydrolysis of lipoprotein triglyceride, is known to bind both LDL and arterial PG. In the presence of LpL, cellular internalization and degradation of LDL is enhanced by a pathway initiated by interaction of LDL with a cell surface heparan sulfate proteoglycan. To determine whether LpL enhances the binding of LDL to arterial chondroitin sulfate (CS)PG and dermatan sulfate (DS)PG, the major extracellular PG of the artery wall, a microtiter plate assay was used to study LpL-PG-LDL interactions. Binding of LDL to both CSPG and DSPG was increased in the presence of LpL but differential effects were seen for the two PG. LpL enhanced the binding of LDL to CSPG a maximum of 20% and to DSPG a maximum of 40%. Heparin displacement of PG binding suggested a greater binding strength for DSPG-LpL-LDL with 0.25 micrograms heparin required to displace 50% of DSPG compared to 0.01 micrograms to displace 50% of CSPG. The greater enhancement of DSPG-LDL interaction by LpL is of particular interest since increases in DSPG correlate with the accumulation of aortic cholesterol. These data suggest that lipoprotein lipase may enhance the interaction of plasma low density lipoprotein with arterial chondroitin sulfate proteoglycan and dermatan sulfate proteoglycan and thus facilitate low density lipoprotein retention in the artery wall. PMID:8371063

Edwards, I J; Goldberg, I J; Parks, J S; Xu, H; Wagner, W D



High-density lipoprotein (HDL3)-associated alpha-tocopherol is taken up by HepG2 cells via the selective uptake pathway and resecreted with endogenously synthesized apo-lipoprotein B-rich lipoprotein particles.  

PubMed Central

alpha-Tocopherol (alphaTocH) is transported in association with lipoproteins in the aqueous milieu of the plasma. Although up to 50% of circulating alphaTocH is transported by high-density lipoproteins (HDLs), little is known about the mechanisms of uptake of HDL-associated alphaTocH. During the current study, human apolipoprotein (apo)E-free HDL subclass 3 (HDL3) labelled with [14C]alphaTocH was used to investigate uptake mechanisms of HDL3-associated alphaTocH by a permanent hepatoblastoma cell line (HepG2). HDL3-associated alphaTocH was taken up independently of HDL3 holoparticles in excess of apoA-I comparable with the non-endocytotic delivery of cholesteryl esters to cells termed the 'selective' cholesteryl ester uptake pathway. Experiments with unlabelled HDL3 demonstrated net mass transfer of alphaTocH to HepG2 cells. Time-dependent studies with [14C]alphaTocH-labelled HDL3 revealed tracer uptake in 80-fold excess of apoA-I and in 4-fold excess of cholesteryl linoleate. In addition to HLDs, low-density lipoprotein (LDL)-associated alphaTocH was also taken up in excess of holoparticles, although to a lesser extent. These findings were confirmed with unlabelled lipoprotein preparations, in which HDL3 displayed a 2- to 3-fold higher alphaTocH donor efficiency than LDLs (lipoproteins adjusted for equal amounts of alphaTocH). An important factor affecting particle-independent uptake of alphaTocH was the cellular cholesterol content (a 2-fold increase in cellular cholesterol levels resulted in a 2.3-fold decrease in uptake). Pulse-chase studies demonstrated that some of the HDL3-associated alphaTocH taken up independently of holoparticle uptake was resecreted along with a newly synthesized apoB-containing lipoprotein fraction. PMID:9576851

Goti, D; Reicher, H; Malle, E; Kostner, G M; Panzenboeck, U; Sattler, W



Radiotracers for low density lipoprotein biodistribution studies in vivo: technetium-99m low density lipoprotein versus radioiodinated low density lipoprotein preparations  

Microsoft Academic Search

In an attempt to characterize the in vivo behavior of (99mTc) low density lipoprotein (LDL), biodistribution studies were performed in normal and hypercholesterolemic (HC) rabbits. In normal rabbits, 24 hr after the injection of (99mTc)LDL, 99mTc activity accumulated mainly in adrenal glands, spleen, liver, and kidney. In HC rabbits, however, there was a marked reduction of 99mTc activity in these

Shankar Vallabhajosula; Michael Paidi; Juan Jose Badimon; Ngoc-Anh Le; Stanley J. Goldsmith; Valentin Fuster; Henry N. Ginsberg



Alcohol dose and low density lipoprotein heterogeneity in squirrel monkeys (Saimiri sciureus).  


The present study was designed to determine whether normolipidemic male squirrel monkeys (Saimiri sciureus) exhibit low density lipoprotein (LDL) heterogeneity similar to that observed in humans and if present, whether LDL subfractions are altered by consumption of low vs. high dose ethanol (EtOH). Primates were divided into three groups designated control, low, and high EtOH and fed isocaloric liquid diets containing 0%, 12% and 24% of calories as EtOH, respectively, for 6 months. The 12% EtOH caloric level resulted in a modest, non-significant increase in high density lipoprotein (HDL) cholesterol and no change in LDL cholesterol or plasma apolipoprotein B (apo B), while the 24% dose produced significant elevations in plasma, LDL and HDL cholesterol and apo B. Using a single-spin density gradient ultracentrifugation procedure developed for humans, three distinct LDL subclasses designated LDL1a (d = 1.031 g/ml), LDL1b (d = 1.038 g/ml) and LDL 2 (d = 1.046 g/ml) were isolated from all three treatment groups. Monkey LDL subfractions were nearly identical to very light, light and heavy LDL subspecies isolated from human plasma in terms of their: (1) isopycnic densities following ultracentrifugation; (2) co-migration as single bands with beta-electrophoretic mobility in cellulose acetate and agarose electrophoretic gels; (3) size-dependent migration pattern in polyacrylamide gradient electrophoretic gels; (4) co-migration as a single band corresponding to apo B-100, following SDS polyacrylamide gel electrophoresis; and (5) decrease in total cholesterol/protein ratios with increasing LDL subclass density. Although there were no treatment differences in LDL particle size, within each treatment group, mean particle size for each LDL subfraction was significantly different from every other subfraction. Low (12%) dose alcohol had no effect on LDL subfraction mass relative to controls while high alcohol consumption resulted in marked increases in all lipid (except triglyceride) and protein of the larger, buoyant LDL subspecies (LDL1a and LDL1b). Moreover, the best correlation between plasma apo B and LDL subfraction total mass was demonstrated with LDL1b (r = 0.735). Since neither the lipid nor the protein concentration of the small, dense, purportedly more atherogenic, LDL2 changed with the 24% EtOH dose, we propose that the LDL subfraction alterations associated with high alcohol intake in squirrel monkeys (increased LDL1a, increased LDL1b, LDL2 no effect) may represent a compensatory response to modulate the overall atherogenic lipoprotein profile associated with elevations in total LDL cholesterol and plasma apolipoprotein B. PMID:1632875

Hojnacki, J L; Cluette-Brown, J E; Dawson, M; Deschenes, R N; Mulligan, J J



Effect of Obesity on High-density Lipoprotein Metabolism  

Microsoft Academic Search

Reduced levels of high-density lipoproteins (HDL) in non-obese and obese states are associated with increased risk for the development of coronary artery disease. Therefore, it is imperative to determine the mechanisms responsible for reduced HDL in obese states and, conversely, to examine therapies aimed at increasing HDL levels in these individuals. This paper examines the multiple causes for reduced HDL

Shirya Rashid; Jacques Genest



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 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.



High Density Lipoprotein Structural Changes and Drug Response in Lipidomic Profiles following the Long-Term  

E-print Network

and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have), decreased high-density lipoprotein cholesterol (HDL-C), small dense low-density lipoprotein (LDL) particles

Kaski, Samuel


HIV infection and high density lipoprotein metabolism.  


HIV infection and its treatment are associated with dyslipidemia, including hypoalphalipoproteinemia, and increased risk of cardiovascular disease. Parameters of HDL metabolism in HIV-positive patients were investigated in a cross-sectional study. The following groups of subjects were selected: (i) 25 treatment-naïve HIV-infected patients or HIV-infected patients on long therapy break, (ii) 28 HIV-infected patients currently treated with protease inhibitors, and (iii) 33 HIV-negative subjects. Compared to the HIV-negative group, all groups of HIV-infected patients were characterized by significantly elevated triglyceride and apolipoprotein B levels, mass and activity of lecithin cholesterol acyl transferase and cholesteryl ester transfer protein (p<0.01). Total and LDL cholesterol was lower in treatment-naïve HIV-infected group only. HDL cholesterol and prebeta(1)-HDL were significantly lower in all HIV-infected groups (p<0.05), while mean levels of apolipoprotein A-I (apoA-I) and ability of plasma to promote cholesterol efflux were similar in all groups. We found a positive correlation between apoA-I and levels of CD4+ cells (r(2)=0.3, p<0.001). Plasma level of phospholipid transfer protein was reduced in the group on antiretroviral therapy. Taken together these results suggest that HIV infection is associated with modified HDL metabolism re-directing cholesterol to the apoB-containing lipoproteins and likely reducing the functionality of reverse cholesterol transport. PMID:18054941

Rose, Honor; Hoy, Jennifer; Woolley, Ian; Tchoua, Urbain; Bukrinsky, Michael; Dart, Anthony; Sviridov, Dmitri



Metabolism of lipoproteins in nonhuman primates. Studies on the origin of low density lipoprotein apoprotein in the plasma of the squirrel monkey.  


The plasma of squirrel monkeys contains extremely low levels of very low density lipoproteins. The delipidated apoproteins from the different lipoprotein density classes of this species show a heterogeneity similar to that of man and the rat. The biosynthesis of the apoproteins of squirrel monkey lipoproteins was studied in fasted normal and Triton WR1339-treated animals. After intravenous injection of [3-H] leucine, maximal labeling of very low density lipoproteins occurred after 1 h, intermediate density lipoproteins (d 1.006--1.019) in 2 h, and low density lipoproteins after 3 h. At all times, however, low density lipoproteins had the greatest percentage of radioactivity. Polyacrylamide gel electrophoresis revealed that the apoprotein B moiety of very low density and intermediate density lipoproteins contained 62% and 81% of the total radioactivity in these lipoproteins whereas the fast-migrating peptides were minimally labeled. In monkeys injected with Triton WR1339, 70--80% of the radioactivity incorporated into d smaller than 1.063 lipoproteins was in very low density lipoproteins with only 10--15% in intermediate and low density lipoproteins. After injection of 3-H-labeled very low density lipoproteins and [14-C] leucine into Triton-treated monkeys, catabolism of 3-H-labeled very low density lipoprotein to intermediate and low density lipoproteins was small and was significantly less than corresponding values for the incorporation of [14-C] leucine. Thus, breakdown of very low density lipoproteins could not account for all the labeled apoprotein B present in the intermediate and low density lipoprotein fractions. The results indicate that most, but not all, of the newly synthesized apoprotein B enters plasma in very low density lipoproteins and that the low concentrations of this lipoprotein in squirrel monkey plasma are a consequence of its rapid turnover. PMID:164942

Illingworth, D R



Effects of human low and high density lipoproteins on the binding of rat intermediate density lipoproteins to rat liver membranes  

SciTech Connect

Upon incubation with rat liver membranes, radioiodinated rat intermediate density lipoproteins (IDL) interacted with at least two binding sites having a low and a high affinity as demonstrated by the curvilinear Scatchard plots obtained from the specific binding data. The purpose of our work was to identify the nature of these binding sites. Human low density lipoproteins (LDL), contain apolipoprotein B only, and human high density lipoproteins (HDL3), containing neither apolipoprotein B nor E, were both capable of decreasing the specific binding of rat /sup 125/I-IDL. The Scatchard analysis clearly revealed that only the low affinity component was affected by the addition of these human lipoproteins. In fact, the low affinity binding component gradually decreased as the amount of human LDL or HDL3 increased in the binding assay. At a 200-fold excess of human LDL or HDL3, the low affinity binding was totally masked, and the Scatchard plot of the specific /sup 125/I-IDL binding became linear. Only the high affinity binding component was left, enabling a precise measurement of its binding parameters. In a series of competitive displacement experiments in which the binding assay contained a 200-fold excess of human LDL or HDL3, only unlabeled rat IDL effectively displaced the binding of rat /sup 125/I-IDL. We conclude that the low affinity binding of rat IDL to rat liver membranes is due to weak interactions with unspecified lipoprotein binding sites. The camouflage of these sites by human lipoproteins makes possible the study of IDL binding to the high affinity component which likely represents the combined effect of IDL binding to both the remnant and the LDL receptors.

Brissette, L.; Nol, S.P.



The low-density lipoprotein receptor: ligands, debates and lore  

Microsoft Academic Search

Like pieces belonging to a large mosaic, the structures of low-density lipoprotein receptor (LDL-R) modules have been elucidated one by one in recent years. LDL-Rs localized on hepatocytes play an important role in removing cholesterol-transporting LDL particles from the plasma by receptor-mediated endocytosis. Key steps in this process involve the LDL-R binding LDL at neutral pH at the cell surface

Gabby Rudenko; Johann Deisenhofer



Low-Density Lipoprotein Cholesterol and Coronary Artery Disease  

Microsoft Academic Search

Except for age, dyslipidemia is the most important predictive factor for coronary artery disease (CAD) (1). The strong, independent, continuous, and graded relationship between total cholesterol (TC) levels, or low-density lipoprotein\\u000a (LDL)-cholesterol (C) level and the risk of CAD events has been clearly demonstrated world wide in men and women and in all\\u000a age groups (2–6). High cholesterol levels are

JoAnne Micale Foody


Synthesis, transport, and processing of apolipoproteins of high density lipoproteins  

Microsoft Academic Search

Cell biology methods have greatly influenced the elucidation of the biosynthetic pathways of apolipoproteins. In vitro and tissue culture systems allow the study, to a large extent, of the process of synthesis, intracellular processing, secretion, and extracellular processing of the major high density lipoprotein apoproteins apoA-I and A-I1 and also of a minor component, apoA-IV. Whereas the latter apoprotein is

Wilhelm Stoffel


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.



Oxidation of low-density lipoprotein by hemoglobin-hemichrome.  


Hemoglobin and myoglobin are inducers of low-density lipoprotein oxidation in the presence of H(2)O(2). The reaction of these hemoproteins with H(2)O(2) result in a mixture of protein products known as hemichromes. The oxygen-binding hemoproteins function as peroxidases but as compared to classic heme-peroxidases have a much lower activity on small sized and a higher one on large sized substrates. A heme-globin covalent adduct, a component identified in myoglobin-hemichrome, was reported to be the cause of myoglobin peroxidase activity on low-density lipoprotein. In this study, we analyzed the function of hemoglobin-hemichrome in low-density lipoprotein oxidation. Oxidation of lipids was analyzed by formation of conjugated diene and malondialdehyde; and oxidation of Apo-B protein was analyzed by development of bityrosine fluorescence and covalently cross-linked protein. Hemoglobin-hemichrome has indeed triggered oxidation of both lipids and protein, but unlike myoglobin, hemichrome has required the presence of H(2)O(2). In correlation to this, we found that unlike myoglobin, hemichrome formed by hemoglobin/H(2)O(2) does not contain a globin-heme covalent adduct. Nevertheless, hemoglobin-hemichrome remains oxidatively active towards LDL, indicating that other components of the oxidatively denatured hemoglobin should be considered responsible for its hazardous activity in vascular pathology. PMID:12531248

Bamm, Vladimir Varlen; Tsemakhovich, Vladimir Abraham; Shaklai, Nurith



Interaction of low density lipoproteins with human aortic elastin.  


Interaction between lipoproteins and elastin in the arterial wall may play an important role in atherosclerotic lipid deposition, but binding affinities and other characteristics of the interaction have not been determined previously. Elastin was isolated by hot alkali treatment of human aortic tissue. At 4 degrees C, radioiodinated human low density lipoprotein (LDL) bound to more than one class of binding sites on elastin. Sites of highest affinity had an apparent dissociation constant of 3.6 x 10(-8) M. Total binding at an LDL concentration of 50 micrograms/ml ranged from 4 to 50 ng LDL protein/mg elastin. The binding was relatively specific, since binding was competitively inhibited by LDL and apo E-containing high density lipoprotein (HDL) but only modestly by HDL3. Atherosclerotic elastin exhibited a twofold to fourfold higher capacity for binding LDL, but a reduced affinity. At 37 degrees C, normal elastin exhibited an initial rapid binding of LDL, with a slower linear phase of binding over a 15-hour period, indicating an additional complex process at this temperature. Consideration of the expected LDL concentrations in the arterial intima, in comparison with binding affinities, suggests that LDL binding to elastin probably occurs in the intima and may foster atherosclerotic lipid deposition. PMID:1987988

Podet, E J; Shaffer, D R; Gianturco, S H; Bradley, W A; Yang, C Y; Guyton, J R



Indicators of the atherogenic lipoprotein phenotype measured with density gradient ultracentrifugation predict changes in carotid intima-media thickness in men and women  

PubMed Central

Objective Progression of carotid intima-media thickness (CIMT) is a surrogate indicator for the early stages of atherosclerosis. Methods The study investigated relationships between baseline lipoprotein cholesterol, triglyceride (TG), and apolipoprotein (Apo) B levels assessed with density gradient ultracentrifugation (DGU) and progression of posterior wall common CIMT in men (45–75 years of age) and women (55–74 years of age) in the control arm of a clinical trial. Participants had baseline posterior wall CIMT 0.7–2.0 mm, without significant stenosis. CIMT was assessed using B-mode ultrasound at baseline, and 12 and ~18 months. A DGU cholesterol panel that assessed the major lipoprotein classes and subclasses, plus triglycerides, lipoprotein (a) cholesterol, low-density lipoprotein (LDL) peak time (inversely related to LDL particle density), and Apo B were performed on fasting baseline samples. Apo B was also measured using an enzyme linked immunosorbent assay. Results Baseline CIMT was inversely associated (P < 0.001) with CIMT progression. After adjustment for baseline CIMT, significant predictors of posterior wall CIMT progression in linear regression analyses included LDL peak time (inverse, P = 0.045), total high-density lipoprotein cholesterol (HDL-C) (inverse, P = 0.001), HDL2-C (inverse, P = 0.005), HDL3-C (inverse, P = 0.003), very low-density lipoprotein (VLDL)-C (P = 0.037), and VLDL1+2-C (P = 0.016). Conclusion These data indicate that DGU-derived indicators of the “atherogenic lipoprotein phenotype,” including increased TG-rich lipoprotein cholesterol, lower HDL-C and HDL-C subfractions, and a greater proportion of LDL-C carried by more dense LDL particles, are associated with CIMT progression in men and women at moderate risk for coronary heart disease. PMID:22272073

Maki, Kevin C; Dicklin, Mary R; Davidson, Michael H; Mize, Patrick D; Kulkarni, Krishnaji R



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

Technology Transfer Automated Retrieval System (TEKTRAN)

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


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

Code of Federal Regulations, 2012 CFR

...lipoprotein immunological test system. 866.5600 Section...DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Immunological Test Systems § 866.5600 Low-density...lipoprotein immunological test system is a device that consists...lipoprotein in serum and other body fluids....



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

Code of Federal Regulations, 2013 CFR

...lipoprotein immunological test system. 866.5600 Section...DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Immunological Test Systems § 866.5600 Low-density...lipoprotein immunological test system is a device that consists...lipoprotein in serum and other body fluids....



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

Code of Federal Regulations, 2011 CFR

...lipoprotein immunological test system. 866.5600 Section...DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Immunological Test Systems § 866.5600 Low-density...lipoprotein immunological test system is a device that consists...lipoprotein in serum and other body fluids....



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

Code of Federal Regulations, 2014 CFR

...lipoprotein immunological test system. 866.5600 Section...DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Immunological Test Systems § 866.5600 Low-density...lipoprotein immunological test system is a device that consists...lipoprotein in serum and other body fluids....



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

Code of Federal Regulations, 2010 CFR

...lipoprotein immunological test system. 866.5600 Section...DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Immunological Test Systems § 866.5600 Low-density...lipoprotein immunological test system is a device that consists...lipoprotein in serum and other body fluids....



High Density Lipoprotein and it’s Dysfunction  

PubMed Central

Plasma high-density lipoprotein cholesterol(HDL-C) levels do not predict functionality and composition of high-density lipoprotein(HDL). Traditionally, keeping levels of low-density lipoprotein cholesterol(LDL-C) down and HDL-C up have been the goal of patients to prevent atherosclerosis that can lead to coronary vascular disease(CVD). People think about the HDL present in their cholesterol test, but not about its functional capability. Up to 65% of cardiovascular death cannot be prevented by putative LDL-C lowering agents. It well explains the strong interest in HDL increasing strategies. However, recent studies have questioned the good in using drugs to increase level of HDL. While raising HDL is a theoretically attractive target, the optimal approach remains uncertain. The attention has turned to the quality, rather than the quantity, of HDL-C. An alternative to elevations in HDL involves strategies to enhance HDL functionality. The situation poses an opportunity for clinical chemists to take the lead in the development and validation of such biomarkers. The best known function of HDL is the capacity to promote cellular cholesterol efflux from peripheral cells and deliver cholesterol to the liver for excretion, thereby playing a key role in reverse cholesterol transport (RCT). The functions of HDL that have recently attracted attention include anti-inflammatory and anti-oxidant activities. High antioxidant and anti-inflammatory activities of HDL are associated with protection from CVD. This review addresses the current state of knowledge regarding assays of HDL functions and their relationship to CVD. HDL as a therapeutic target is the new frontier with huge potential for positive public health implications. PMID:22888373

Eren, Esin; Yilmaz, Necat; Aydin, Ozgur



New therapies for reducing low-density lipoprotein cholesterol.  


Although the past 4 decades have been the most productive in transitioning from an low-density lipoprotein cholesterol (LDL-C) hypothesis to demonstration of clinical benefit, cardiovascular disease remains a major cause of mortality and morbidity. It is fortunate that most of the effective lipid-lowering drugs, the statins, have become generic and inexpensive. However, there remains a large unmet medical need for new and effective agents that are also well tolerated and safe, especially for patients unable to either tolerate statins or achieve optimal LDL-C on current therapies. It is likely that the agents discussed in this review will fill that need. PMID:25432394

Stein, Evan A; Raal, Frederick J



Plasma very low density lipoproteins contain a single molecule of apolipoprotein 6  

Microsoft Academic Search

Rat and human very low density lipoproteins (VLDL) were fractionated by zonal ultracentrifugation, yielding sharply defined fractions with narrow sedimenta- tion limits. Sedimentation coefficients for the individual fractions were determined at two densities with the analytical ultracentrifuge, and the results were analyzed to yield buoy- ant densities and molecular weights for the particles in each fraction. For the rat lipoproteins,

J. Elovson; J. E. Chatterton; G. T. Bell; V. N. Schumaker; M. A. Reuben; D. L. Puppione; J. R. Reeve


Protein carbamylation renders high-density lipoprotein dysfunctional  

PubMed Central

Aim Carbamylation of proteins through reactive cyanate has been demonstrated to predict an increased cardiovascular risk. Cyanate is formed in vivo by break-down of urea and at sites of inflammation by the phagocyte protein myeloperoxidase. Since myeloperoxidase (MPO) associates with high-density lipoprotein (HDL) in human atherosclerotic intima, we examined in the present study whether cyanate specifically targets HDL. Results Mass spectrometry analysis revealed that protein carbamylation is a major post-translational modification of HDL. The carbamyllysine content of lesion derived HDL was more than 20-fold higher in comparison to 3-chlorotyrosine levels, a specific oxidation product of MPO. Notable, the carbamyllysine content of lesion-derived HDL was 5 to 8-fold higher when compared to lesion derived low-density lipoprotein (LDL) or total lesion protein and increased with lesion severity. Importantly, the carbamyllysine content of HDL, but not of LDL, correlated with levels of 3-chlorotyrosine, suggesting 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. Conclusion The present results raise the possibility that HDL carbamylation contributes to foam cell formation in atherosclerotic lesions. PMID:21235354



High density lipoprotein metabolism in low density lipoprotein receptor-deficient mice.  


The LDL receptor (LDLR) and scavenger receptor class B type I (SR-BI) play physiological roles in LDL and HDL metabolism in vivo. In this study, we explored HDL metabolism in LDLR-deficient mice in comparison with WT littermates. Murine HDL was radiolabeled in the protein ((125)I) and in the cholesteryl ester (CE) moiety ([(3)H]). The metabolism of (125)I-/[(3)H]HDL was investigated in plasma and in tissues of mice and in murine hepatocytes. In WT mice, liver and adrenals selectively take up HDL-associated CE ([(3)H]). In contrast, in LDLR(-/-) mice, selective HDL CE uptake is significantly reduced in liver and adrenals. In hepatocytes isolated from LDLR(-/-) mice, selective HDL CE uptake is substantially diminished compared with WT liver cells. Hepatic and adrenal protein expression of lipoprotein receptors SR-BI, cluster of differentiation 36 (CD36), and LDL receptor-related protein 1 (LRP1) was analyzed by immunoblots. The respective protein levels were identical both in hepatic and adrenal membranes prepared from WT or from LDLR(-/-) mice. In summary, an LDLR deficiency substantially decreases selective HDL CE uptake by liver and adrenals. This decrease is independent from regulation of receptor proteins like SR-BI, CD36, and LRP1. Thus, LDLR expression has a substantial impact on both HDL and LDL metabolism in mice. PMID:24954421

Rinninger, Franz; Heine, Markus; Singaraja, Roshni; Hayden, Michael; Brundert, May; Ramakrishnan, Rajasekhar; Heeren, Joerg



Achieving Secondary Prevention Low-Density Lipoprotein Particle Concentration Goals Using Lipoprotein Cholesterol-Based Data  

PubMed Central

Background Epidemiologic studies suggest that LDL particle concentration (LDL-P) may remain elevated at guideline recommended LDL cholesterol goals, representing a source of residual risk. We examined the following seven separate lipid parameters in achieving the LDL-P goal of <1000 nmol/L goal for very high risk secondary prevention: total cholesterol to HDL cholesterol ratio, TC/HDL, <3; a composite of ATP-III very high risk targets, LDL-C<70 mg/dL, non-HDL-C<100 mg/dL and TG<150 mg/dL; a composite of standard secondary risk targets, LDL-C<100, non-HDL-C<130, TG<150; LDL phenotype; HDL-C?40; TG<150; and TG/HDL-C<3. Methods We measured ApoB, ApoAI, ultracentrifugation lipoprotein cholesterol and NMR lipoprotein particle concentration in 148 unselected primary and secondary prevention patients. Results TC/HDL-C<3 effectively discriminated subjects by LDL-P goal (F?=?84.1, p<10?6). The ATP-III very high risk composite target (LDL-C<70, nonHDL-C<100, TG<150) was also effective (F?=?42.8, p<10?5). However, the standard secondary prevention composite (LDL-C<100, non-HDL-C<130, TG<150) was also effective but yielded higher LDL-P than the very high risk composite (F?=?42.0, p<10?5) with upper 95% confidence interval of LDL-P less than 1000 nmol/L. TG<150 and TG/HDL-C<3 cutpoints both significantly discriminated subjects but the LDL-P upper 95% confidence intervals fell above goal of 1000 nmol/L (F?=?15.8, p?=?0.0001 and F?=?9.7, p?=?0.002 respectively). LDL density phenotype neared significance (F?=?2.85, p?=?0.094) and the HDL-C cutpoint of 40 mg/dL did not discriminate (F?=?0.53, p?=?0.47) alone or add discriminatory power to ATP-III targets. Conclusions A simple composite of ATP-III very high risk lipoprotein cholesterol based treatment targets or TC/HDL-C ratio <3 most effectively identified subjects meeting the secondary prevention target level of LDL-P<1000 nmol/L, providing a potential alternative to advanced lipid testing in many clinical circumstances. PMID:22479428

Mathews, Simon C.; Mallidi, Jaya; Kulkarni, Krishnaji; Toth, Peter P.; Jones, Steven R.



SELDI-TOF mass spectrometry of High-Density Lipoprotein  

PubMed Central

Background High-Density Lipoprotein (HDL), one of the main plasma lipoproteins, serves as a docking station for proteins involved in inflammation, coagulation, and lipid metabolism. Methods To elucidate the protein composition of HDL, we employed SELDI-TOF mass spectrometry as a potential high-throughput proteomic candidate for protein profiling of HDL. HDL derived from normolipemic individuals was captured on PS20 protein-chips using covalently bound antibodies against apo A-I or A-II. Results After optimisation, on-chip capture of HDL particles directly from plasma or from pre-purified HDL resulted in comparable fingerprints confirming specific capture of HDL. Depending on the capture antibody some differences in the fingerprint were observed. The most detailed fingerprint was observed up to 50 kDa; approximately 95 peaks were detected in the 3–50 kDa molecular mass range. Between 50 and 160 kDa, 27 more peaks were detected. Conclusion Based on these results, SELDI-TOF MS may be a suitable high-throughput candidate for HDL protein profiling and marker search. This approach may be used to i) investigate the underlying mechanisms that lead to increased atherothrombotic risk and ii) to investigate the atherothrombotic state of an individual. PMID:17822561

Levels, Johannes HM; Bleijlevens, Boris; Rezaee, Farhad; Aerts, Johannes MFG; Meijers, Joost CM



Isolation of high density lipoproteins from rat intestinal epithelial cells.  

PubMed Central

Previous studies have defined forms of high density lipoproteins (HDL) in rat mesenteric lymph, suggesting that they have a secretory origin. This study describes the isolation and characterization of intestinal intracellular HDL. Two preparations were made as follows: (a) Rat enterocytes were isolated and a Golgi organelle fraction was prepared. (b) Cell homogenates were subjected to nitrogen cavitation and a cytoplasmic fraction was prepared. Lipoproteins were isolated from both preparations by sequential ultracentrifugation. When the HDL fraction (1.07-1.21 g/ml) was subjected to isopyknic density gradient ultracentrifugation, a peak of apoproteins A-I and B (apoA-I and apoB, respectively) was found at a density of 1.11-1.14 g/ml. Electron microscopy of the fraction showed spherical particles ranging in size from 6 to 13 nm. Immunoelectrophoresis revealed a precipitin arc in the alpha region against apoA-I which extended into the pre-beta region where a precipitin arc against apoB was also seen. ApoB antisera depleted the pre-beta particles whereas the alpha migrating particles remained. Lipid analysis of the whole HDL fraction revealed phospholipid, cholesteryl ester, and triglyceride as the major lipids. [3H]leucine was then administered into the duodenum and a radiolabeled intracellular HDL fraction was isolated. The newly synthesized apoproteins of the HDL fraction, as determined by gel electrophoresis, were apoB, apoA-I, and apolipoprotein A-IV (ApoA-IV). Immunoprecipitation of the apoB particles revealed apoA-I and apoA-IV in the supernatant. These data demonstrate that there are at least two intracellular intestinal forms of HDL particles, one of which contains apoB. The other particle contains apoA-I and apoA-IV, has alpha mobility, is spherical, and resembles a particle found in the lymph. Images PMID:3965504

Magun, A M; Brasitus, T A; Glickman, R M



The role of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in comparison with whole egg yolk for sperm cryopreservation in rhesus monkeys  

Microsoft Academic Search

Low-density lipoprotein (LDL) extracted from hen egg yolk has recently been considered to be superior to whole egg yolk in sperm cryopreservation of various animal species. Meanwhile, there was a notion that high-density lipoprotein (HDL) in egg yolk may have a negative effect on post-thaw survival. The role of LDL and HDL in sperm cryopreservation of rhesus monkeys has not

Qiao-Xiang Dong; Sarah E Rodenburg; Dana Hill; Catherine A VandeVoort



Cryoelectron microscopy of low density lipoprotein in vitreous ice.  

PubMed Central

In this report, images of low density lipoprotein (LDL) in vitreous ice at approximately 30 A resolution are presented. These images show that LDL is a quasi-spherical particle, approximately 220-240 A in diameter, with a region of low density (lipid) surrounded by a ring (in projection) of high density believed to represent apolipoprotein B-100. This ring is seen to be composed of four or five (depending on view) large regions of high density material that may represent protein superdomains. Analysis of LDL images obtained at slightly higher magnification reveals that areas of somewhat lower density connect these regions, in some cases crossing the projectional interiors of the LDL particles. Preliminary image analysis of LDL covalently labeled at Cys3734 and Cys4190 with 1.4-nm Nanogold clusters demonstrates that this methodology will provide an important site-specific marker in studies designed to map the organization of apoB at the surface of LDL. Images FIGURE 1 FIGURE 2 FIGURE 3 FIGURE 4 FIGURE 6 PMID:7612855

Spin, J M; Atkinson, D



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



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

E-print Network

Knowledge-Driven Analysis Identifies a Gene­Gene Interaction Affecting High-Density Lipoprotein-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease on HDL-C levels (Bonferroni corrected Pc = 0.002). Using an adaptive locus-based validation procedure, we

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 oxidation: in vitro susceptibility and potential in vivo consequences  

Microsoft Academic Search

Elevated levels of plasma high density lipoprotein (HDL) are strongly predictive of protection against atherosclerotic vascular disease. HDL particles likely have several beneficial actions in vivo, including the initiation of reverse cholesterol transport. The apparent importance of oxidative modification of low density lipoprotein in atherogenesis raises the question of how oxidative modification of HDL might affect its cardioprotective actions. HDL

Gordon A Francis



The low-density lipoprotein receptor: ligands, debates and lore.  


Like pieces belonging to a large mosaic, the structures of low-density lipoprotein receptor (LDL-R) modules have been elucidated one by one in recent years. LDL-Rs localized on hepatocytes play an important role in removing cholesterol-transporting LDL particles from the plasma by receptor-mediated endocytosis. Key steps in this process involve the LDL-R binding LDL at neutral pH at the cell surface and, after internalization, releasing it again at acidic pH in the endosomes. How the modules of the LDL-R might interact within the intact receptor to carry out ligand binding and release has been revealed by the recent crystal structure of the extracellular domain of the LDL-R. PMID:14675545

Rudenko, Gabby; Deisenhofer, Johann



Serum concentration of high density lipoproteins (HDLs) in leishmaniotic dogs.  


In order to assess whether the concentration of high density lipoproteins (HDLs) changes in leishmaniotic dogs before and after treatment, HDL cholesterol (HDL-Chol and HDL%), C reactive protein (CRP) and activity of the antioxidant enzyme paraoxonase (PON-1) were measured in sera from 10 controls and 10 leishmaniotic dogs. Seven of these latter were sampled also 3, 7, 14, 21 and 28 days after treatment with antimonials and allopurinol. HDL-chol, and PON-1 were low in leishmaniotic dogs at admission and increased after treatment. HDL-chol and HDL% correlated positively with PON-1 and negatively with CRP suggesting that HDLs decrease through an oxidative mechanism. Therefore, HDLs may be used to monitor the magnitude of oxidation associated with inflammation in leishmaniotic dogs. PMID:25440996

Ibba, Fabrizio; Rossi, Gabriele; Meazzi, Sara; Giordano, Alessia; Paltrinieri, Saverio



Total and High-Density Lipoprotein Cholesterol in Adults: National Health and Nutrition Examination Survey, 2011-2012  


... Blood Institute. 2002. Carroll MD, Kit BK, Lacher DA. Total and high-density lipoprotein cholesterol in adults: ... 2001. Suggested citation Carroll MD, Kit BK, Lacher DA, Yoon SS. Total and high-density lipoprotein cholesterol in ...


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



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

PubMed Central

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

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



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



Effect of apolipoprotein M on high density lipoprotein metabolism and atherosclerosis in low density lipoprotein receptor knock-out mice.  


To investigate the role of apoM in high density lipoprotein (HDL) metabolism and atherogenesis, we generated human apoM transgenic (apoM-Tg) and apoM-deficient (apoM(-/-)) mice. Plasma apoM was predominantly associated with 10-12-nm alpha-migrating HDL particles. Human apoM overexpression (11-fold) increased plasma cholesterol concentration by 13-22%, whereas apoM deficiency decreased it by 17-21%. The size and charge of apoA-I-containing HDL in plasma were not changed in apoM-Tg or apoM(-/-) mice. However, in plasma incubated at 37 degrees C, lecithin:cholesterol acyltransferase-dependent conversion of alpha- to pre-alpha-migrating HDL was delayed in apoM-Tg mice. Moreover, lecithin: cholesterol acyltransferase-independent generation of pre-beta-migrating apoA-I-containing particles in plasma was increased in apoM-Tg mice (4.2 +/- 1.1%, p = 0.06) and decreased in apoM(-/-) mice (0.5 +/- 0.3%, p = 0.03) versus controls (1.8 +/- 0.05%). In the setting of low density lipoprotein receptor deficiency, apoM-Tg mice with approximately 2-fold increased plasma apoM concentrations developed smaller atherosclerotic lesions than controls. The effect of apoM on atherosclerosis may be facilitated by enzymatic modulation of plasma HDL particles, increased cholesterol efflux from foam cells, and an antioxidative effect of apoM-containing HDL. PMID:18006500

Christoffersen, Christina; Jauhiainen, Matti; Moser, Markus; Porse, Bo; Ehnholm, Christian; Boesl, Michael; Dahlbäck, Björn; Nielsen, Lars Bo



Cholesteryl Ester Accumulation in Macrophages Incubated with Low Density Lipoprotein Pretreated with Cigarette Smoke Extract  

Microsoft Academic Search

Although cigarette smoking is one of the major risk factors for atherosclerosis and coronary heart disease, the precise mechanisms of its adverse effects have not been fully elucidated. We incubated low density lipoprotein (LDL) with cigarette smoke (CS) extract and examined the incorporation of the lipoprotein by macrophages in vitro. When incubated with macrophages, LDL pretreated with CS extract (100

Masayuki Yokode; Toru Kita; Hidenori Arai; Chuichi Kawai; Shuh Narumiya; Motohatsu Fujiwara



Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins  

Microsoft Academic Search

PLASMA high density lipoproteins (HDL) are a negative risk factor for atherosclerosis. Increased HDL is sometimes clustered in families, but a genetic basis has never been clearly documented1. The plasma cholesteryl ester transfer protein (CETP) catalyses the transfer of cholesteryl ester from HDL to other lipoproteins and therefore might influence HDL levels2. Using monoclonal antibodies, we show that CETP is

Maryanne L. Brown; Akihiro Inazu; Charles B. Hesler; Luis B. Agellon; Chris Mann; Mary E. Whitlock; Yves L. Marcel; Ross W. Milne; Junji Koizumi; Hiroshi Mabuchi; Ryoyu Takeda; Alan R. Tall



Cholesteryl ester transfer protein, low density lipoprotein particle size and intima media thickness in patients with coronary heart disease  

PubMed Central

Cholesteryl ester transfer protein (CETP) plays a key role in reverse cholesterol transport and high density lipoprotein (HDL) metabolism. Predominance of small, dense LDL particles is associated with an increased risk of atherosclerosis and coronary heart disease (CHD). The aim of the study was to determine the potential relationship between the CETP concentration and low density lipoprotein (LDL) particle size and their association with intima media thickness (IMT) in patients with CHD. Lipid parameters, CETP concentration and LDL particle size were determined in 100 healthy subjects (control group) and in 100 patients with CHD, aged 43 to 77 years. Plasma CETP concentrations were measured by an enzyme-linked immuno-sorbent assay with two different monoclonal antibodies. LDL subclasses were separated by nondenaturing polyacrilamide 3-31% gradient gel electrophoresis. CETP concentration was higher in patients compared to controls (2.02 ± 0.75 mg/ml vs. 1.74 ± 0.63 mg/ml, p<0.01). Mean LDL particle size (nm) was significantly smaller in patients than in controls (24.5 ± 1.1 vs. 26.1 ± 0.9; p<0.001). There was no relation between LDL particle size and CETP concentration (r=-0.1807, p=0.072). Age, diastolic blood pressure, CETP concentration and LDL particle size were independent factors for determing IMT by multiple linear regression analysis. They accounted for 35.2 % of the observed variability in IMT. CETP is not an independent contributor of LDL particle size. CETP might play a role in determining lipoprotein distributions, but did not seem to be the sole factor in the formation of small LDL particles. PMID:21875419

Tosheska, Katerina; Labudovic, Danica; Jovanova, Silvana; Jaglikovski, Branko; Alabakovska, Sonja



Effect of a Moderate Fat Diet With and Without Avocados on Lipoprotein Particle Number, Size and Subclasses in Overweight and Obese Adults: A Randomized, Controlled Trial  

PubMed Central

Background Avocados are a nutrient?dense source of monounsaturated fatty acids (MUFA) that can be used to replace saturated fatty acids (SFA) in a diet to lower low density lipoprotein cholesterol (LDL?C). Well?controlled studies are lacking on the effect of avocado consumption on cardiovascular disease (CVD) risk factors. Methods and Results A randomized, crossover, controlled feeding trial was conducted with 45 overweight or obese participants with baseline LDL?C in the 25th to 90th percentile. Three cholesterol?lowering diets (6% to 7% SFA) were fed (5 weeks each): a lower?fat diet (LF: 24% fat); 2 moderate?fat diets (34% fat) provided similar foods and were matched for macronutrients and fatty acids: the avocado diet (AV) included one fresh Hass avocado (136 g) per day, and the moderate?fat diet (MF) mainly used high oleic acid oils to match the fatty acid content of one avocado. Compared with baseline, the reduction in LDL?C and non?high?density lipoprotein (HDL) cholesterol on the AV diet (?13.5 mg/dL, ?14.6 mg/dL) was greater (P<0.05) than the MF (?8.3 mg/dL, ?8.7 mg/dL) and LF (?7.4 mg/dL, ?4.8 mg/dL) diets. Furthermore, only the AV diet significantly decreased LDL particle number (LDL?P, ?80.1 nmol/L, P=0.0001), small dense LDL cholesterol (LDL3+4, ?4.1 mg/dL, P=0.04), and the ratio of LDL/HDL (?6.6%, P<0.0001) from baseline. Conclusions Inclusion of one avocado per day as part of a moderate?fat, cholesterol?lowering diet has additional LDL?C, LDL?P, and non?HDL?C lowering effects, especially for small, dense LDL. Our results demonstrate that avocados have beneficial effects on cardio?metabolic risk factors that extend beyond their heart?healthy fatty acid profile. Clinical Trial Registration URL: Unique identifier: NCT01235832. PMID:25567051

Wang, Li; Bordi, Peter L.; Fleming, Jennifer A.; Hill, Alison M.; Kris?Etherton, Penny M.



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.



Acrolein Impairs the Cholesterol Transport Functions of High Density Lipoproteins  

PubMed Central

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

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



High density lipoprotein/sphingosine-1-phosphate-induced cardioprotection  

PubMed Central

High density lipoprotein (HDL) cholesterol has beneficial effects beyond its atheroprotective function in reverse cholesterol transport, including cardioprotection against ischemia reperfusion (IR) injuries. Two major constituents of HDL, namely the structural protein apolipoprotein AI (apoAI) and the sphingolipid sphingosine-1-phosphate (S1P) appear to contribute to this cardioprotective effect via the activation of intrinsic prosurvival signaling pathways that still remain to be clarified.   Recently, a powerful prosurvival signaling pathway, termed the survivor activating factor enhancement (SAFE) pathway, which involves the activation of signal transducer and activator of transcription 3 (STAT3) and tumor necrosis factor ? (TNF), has been shown to protect against ischemia-reperfusion injuries. The present review summarizes the evidence for the roles of HDL and S1P in cardioprotection and discusses the signaling pathways that have been implicated. It thus provides support for our contention that S1P should be considered in potential formulations of reconstituted HDL (reHDL) that may be tested for cardioprotection against coronary artery disease via the activation of the SAFE pathway. PMID:24058758

Frias, Miguel A.; Lecour, Sandrine; James, Richard W.; Pedretti, Sarah



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

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



The Mechanism of Oxidation-Induced Low-Density Lipoprotein Aggregation: An Analogy to Colloidal Aggregation and Beyond?  

Microsoft Academic Search

Atherosclerosis is a disease initiated by lipoprotein aggregation and deposition in artery walls. In this study, the de novo low-density lipoprotein aggregation process was examined. Nine major intermediates were identified in two stages of the aggregation process. In the aggregation stage, low-density lipoprotein molecules aggregate and form nucleation units. The nucleation units chain together and form linear aggregates. The linear

Shaohua Xu; Binhua Lin



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


Relationship between plasma insulin levels and high density lipoprotein cholesterol levels in healthy men  

Microsoft Academic Search

Summary  Insulin and high density lipoproteins are considered to play a role in the development of atherosclerosis. In order to study whether there was a relationship between endogenous plasma insulin response and high density lipoproteins, an acute intravenous glucose tolerance test (0.5 g glucose\\/kg body weight) was performed in 94 healthy men, aged 20–49 years. Cholesterol and triglyceride levels were measured

M. Stalder; D. Pometta; A. Suenram



Uptake of lipoproteins by in situ perfused rat ovaries: identification of binding sites for high density lipoproteins  

PubMed Central

We have examined the uptake and distribution of 125I-labeled human high density lipoprotein, apolipoprotein E-free (hHDL3), 125I-rat high density lipoprotein (HDL), and human HDL (hHDL) reconstituted with [3H]cholesteryl linoleate after their in situ vascular perfusion to ovaries of gonadotropin-primed immature rats on days 6-9 post human chorionic gonadotropin (hCG)-injection. Some rats were treated with 4- aminopyrazolopyrimidine to reduce plasma lipoproteins and ovarian cholesteryl ester stores. Perfused ovaries were analyzed biochemically and autoradiographically, and progestin content of the ovarian effluent was quantified. Infusion of ovine luteinizing hormone and hHDL increased ovarian progestin secretion severalfold, indicating that the perfused ovary was functional. After perfusion with HDL reconstituted with [3H]cholesteryl linoleate, radioactive progestin appeared in the effluent; thus, sterol carried by exogenous HDL was converted to steroid. At 37 degrees C, uptake of 125I-hHDL3 was greatest after 15 min of perfusion with label. This was decreased by 80% when the perfusion was carried out at 4 degrees C and by 70-95% when excess unlabeled hHDL, but not human low density lipoprotein (hLDL), was included in the perfusate with 125I-hHDL. Aminopyrazolopyrimidine treatment enhanced 125I-hHDL uptake twofold. After perfusion for 15 min with 125I-hHDL3, radioactivity in the ovary was high for 3-30 min of HDL-free wash, then declined 75% by 30-60 min. With light and electron microscope autoradiography, 125I-hHDL3 was localized to corpora lutea, both along luteal cell surfaces and over their cytoplasm. The plasma membrane grains appeared to be associated with segments that lacked bristle coats. Perfusion with 125I-rat HDL produced a similar pattern of labeling. In ovaries perfused with 125I-BSA, silver grains were concentrated over macrophage-like cells but were sparse over luteal cells. We conclude that the in situ perfused rat ovary takes up 125I- hHDL3 by a temperature-dependent, lipoprotein-specific process, and that this lipoprotein is accumulated by luteal cells. PMID:6309865



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



Low Density Lipoprotein transport in the normal human aortic arch  

PubMed Central

Background: To understand the genesis and progression of atherosclerosis is essential to elucidate the blood flow and the transport of molecules in the cardiovascular system. The purpose of this computational study is to elucidate the relationship between low wall shear stress (WSS) - high site concentration of low density lipoproteins (LDL) and atherosclerotic sites in the normal human aortic arch under physiological flow and mass transport conditions. Methods: The numerical simulation couples the flow equations with the transport equation applying realistic boundary conditions at the wall in terms of blood-side concentration. The blood is considered to be non-Newtonian fluid obeying to the power law. Suitable mass transport conditions are specified at the wall. Results: Aortic arch walls are exposed to cholesterolemic environment although the applied mass and flow conditions refer to normal human geometry and normal mass-flow conditions. The luminal surface LDL concentration varies inversely with the WSS. Regions of high LDL luminal surface concentration do not necessarily co-locate to the sites of lowest WSS. Concave sides of the aortic arch exhibit, relatively to the convex sides, elevated concentration of the LDL. The area averaged normalized LDL concentration over the entire normal aortic arch is 1.267. The daughter aortic arch vessels exhibit, relatively to the main aorta, elevated LDL concentrations. Conclusions: The near wall paths of the velocities might be the most important factor for the elevated LDL concentration at areas located either at the vicinity of bifurcations regions or at high curvature regions. Hippokratia 2014; 18 (3): 221-225. PMID:25694755

Soulis, JV; Dimitrakopoulou, M; Giannoglou, GD



Reconstituted High-Density Lipoprotein Modulates Activation of Human Leukocytes  

PubMed Central

An anti-inflammatory effect of reconstituted High Density Lipoprotein (rHDL) has been demonstrated in atherosclerosis and in sepsis models. An increase of adhesion molecules as well as tissue factor expression on endothelial cells in response to inflammatory or danger signals are attenuated by the treatment with rHDL. Here we show the inhibitory effect of rHDL on the activation of human leukocytes in a whole blood assay as well as on monocyte-derived human dendritic cells (DC). Multiplex analysis of human whole blood showed that phytohaemagglutinin (PHA)-induced secretion of the cytokines IL-1?, IL-1RA, IL-2R, IL-6, IL-7, IL-12(p40), IL-15 and IFN-? was inhibited. Furthermore, an inhibitory effect on the production of the chemokines CCL-2, CCL-4, CCL-5, CXCL-9 and CXCL-10 was observed. Activation of granulocytes and CD14+ monocytes by PHA is inhibited dose-dependently by rHDL shown as decreased up-regulation of ICAM-1 surface expression. In addition, we found a strong inhibitory effect of rHDL on toll-like receptor 2 (TLR2)- and TLR4-mediated maturation of DC. Treatment of DC with rHDL prevented the up-regulation of cell surface molecules CD80, CD83 and CD86 and it inhibited the TLR-driven activation of inflammatory transcription factor NF-?B. These findings suggest that rHDL prevents activation of crucial cellular players of cellular immunity and could therefore be a useful reagent to impede inflammation as well as the link between innate and adaptive immunity. PMID:23967171

Kropf, Alain; Miescher, Sylvia; Spycher, Martin O.; Rieben, Robert



Stoichiometry of Reconstituted High-Density Lipoproteins in the Hydrated State Determined by Photon Antibunching  

PubMed Central

Apolipoprotein A-I plays a central role in the solution structure of high-density lipoproteins. Determining the stoichiometry of lipid-bound apo A-I in the hydrated state is therefore fundamental to understanding how high-density lipoproteins form and function. Here, we use the quantum optical phenomenon of photon antibunching to determine the number of apo A-I molecules bound to discoidal lipoproteins and compare this with values obtained by photon-counting histogram analysis. Both the photon antibunching and photon-counting analyses show that reconstituted high-density lipoprotein particles contain two apo A-I molecules, which is in agreement with the commonly accepted double-belt model. PMID:21843489

Ly, Sonny; Petrlova, Jitka; Huser, Thomas; Fore, Samantha; Gao, Tingjuan; Voss, John; Laurence, Ted A.



Enhanced Macrophage Degradation of Low Density Lipoprotein Previously Incubated with Cultured Endothelial Cells: Recognition by Receptors for Acetylated Low Density Lipoproteins  

Microsoft Academic Search

Human low density lipoprotein (LDL) was incubated with an established line of rabbit aortic endothelial cells. Density gradient fractionation showed a time-, concentration-, and temperature-dependent increase in the average density of the LDL (from about 1.036 to as high as 1.070 g\\/ml). Incubation without cells or with other types of cultured cells (fibroblasts, hepatocytes, 3T3-L1 cells) caused no significant change

Tore Henriksen; Eileen M. Mahoney; Daniel Steinberg



Triacylglycerol and very low density lipoprotein secretion into plasma of squirrel monkeys.  


We determined the effects of varying the types and level of dietary fat and cholesterol on the increase in plasma total triacylglycerol concentrations after injection of Triton WR-1339, an inhibitor of lipoprotein lipase, into monkeys that had been subjected to an overnight fast. The monkeys that had been treated with Triton WR-1339 were then given a test meal by intragastric intubation. Dietary cholesterol, high levels of fat and saturated fat in the habitual diet reduced the rate of release of triacylglycerol to plasma in the fasted monkey. We also determined the changes in protein and lipid concentrations of the different lipoprotein fractions. The injection of Triton WR-1339 resulted in a linear increase with time in the concentration of protein and triacylglycerol in the very low density (chylomicron-free and d less than 1.006) lipoproteins, but there was an increase in the ratio of traicylglycerol to protein in that fraction. Most of the increase (96%) in very low density protein was in the B protein. Regardless of the habitual diet, a test meal accentuated the rate of triacylglycerol appearance in whole plasma and in the very low density lipoproteins of Triton WR-1339-treated monkeys, and the rate of increase of the protein component after feeding was slightly higher. Thus the administration of a meal to the fasted Triton WR-1339-treated squirrel monkey further increased the proportion of triacylglycerol in very low density lipoproteins. Although dietary cholesterol and saturated fat in the habitual diet depressed the rate of increase in very low density triacylglycerol during fasting, the rate of protein synthesis was not significantly affected. After administration of a test meal the rates of increase in triacylglycerol and protein in the very low density lipoproteins were similar for monkeys from the different diet groups. Triton WR-1339 administration caused a slight and progressive increase in the intermediate density (d 1.006-1.019) lipoproteins and a marked and progressive decrease in the low density (d 1.019-1.063) lipoproteins. There was an immediate (by 5 min) drop of 70% or more in high density (d 1.063-1.21) lipoprotein protein, but the lipids except triacylglycerol remained unchanged. There was a decrease in both the A (the major fraction) and C proteins. The rates of very low density B protein secretion were comparable to the rates of low density lipoprotein catabolism that had been previously demonstrated for this species. PMID:192300

Portman, O W; Alexander, M; Tanaka, N; Illingworth, D R



Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia  

Microsoft Academic Search

This randomized, double-blind, placebo-controlled trial was conducted in 52 centers in North America to compare the effects of the new, highly effective statin, rosuvastatin, with atorvastatin and placebo in hypercholesterolemic patients. After a 6-week dietary run-in, 516 patients with low-density lipoprotein (LDL) cholesterol ?4.14 mmol\\/L (160 mg\\/dl) and

Michael Davidson; Patrick Ma; Evan A Stein; Antonio M Gotto; Ali Raza; Rohini Chitra; Howard Hutchinson



Effect of proteolysis of low-density serum lipoproteins on their interaction with macrophages  

SciTech Connect

The authors previously postulated, on the basis of changes observed in the structural stability of low-density lipoproteins during treatment with pepsin or aortic cathepsin, that enzymatic modifications may lead to potentiation of the atherogenic properties of the lipoproteins. They also reported that treatment of lipoproteins with trypsin causes an increase in their binding with aortic glycosaminoglycans and to increased degradation by fibroblasts of patients with hereditary hypercholesterolemia. Limited proteolysis of lipoproteins with pepsin facilitated their binding with fibronectin. In this paper the authors investigate the uptake and degradation of low-density lipoproteins by macrophages after their limited hydrolysis by pepsin, an analog of tissue cathepsin D. The lipoproteins were isolated from the serum of healthy blood donors by ultracentrifugation. Iodination of the proteins with I 125 was carried out by the iodine monochloride method. Uptake and retention of the labelled lipoprotein were measured with a gamma counter. The increased uptake of the proteins, partially hydrolized by pepsin, was accompanied by their more intense degradation by macrophages.

Karmanskii, I.M.; Kovaleva, G.G.; Viktorova, L.N.; Shpikiter, V.O.



Transvascular Low-Density Lipoprotein Transport in Patients With Diabetes Mellitus (Type 2) A Noninvasive In Vivo Isotope Technique  

Microsoft Academic Search

Objective—The increased risk of atherosclerosis associated with diabetes cannot be explained by conventional cardiovas- cular risk factors alone. We hypothesized that transvascular lipoprotein transport may be increased in patients with diabetes, possibly explaining increased intimal lipoprotein accumulation and, thus, atherosclerosis. Methods and Results—We developed an in vivo method for measurement of transvascular transport of low density lipoprotein (LDL) and applied

Karen Kornerup; Børge Grønne Nordestgaard; Bo Feldt-Rasmussen; Knut Borch-Johnsen; Kurt Svarre Jensen; Jan Skov Jensen


The low-density lipoprotein receptor family: Genetics, function, and evolution  

Microsoft Academic Search

With ever increasing sophistication in molecular biological approaches, the low-density lipoprotein receptor supergene family\\u000a continues to grow rapidly. From the well-defined key role of these receptors in lipoprotein metabolism, the new members move\\u000a the field into many different and diverse physiologic and developmental areas. We observe an expansion of the functional spectrum\\u000a of the family members, which is due to

Wolfgang Johann Schneider; Johannes Nimpf; Christian Brandes; Mathias Drexler



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



Familial Hypercholesterolaemia Regression Study: a randomised trial of low-density-lipoprotein apheresis  

Microsoft Academic Search

Low-density-lipoprotein (LDL) apheresis has the theoretical advantage over anion-exchange resins and hydroxy-methylglutaryl coenzyme A inhibitors of decreasing lipoprotein(a) as well as LDL. To confirm this advantage, patients with heterozygous familial hypercholesterolaemia and coronary artery disease were randomised to receive LDL apheresis fortnightly (with disposable dextran sulphate\\/cellulose columns) plus simvastatin 40 mg daily, or colestipol 20 g plus simvastatin 40 mg

G. R. Thompson; V. M. G. Maher; Y. Kitano; C. Neuwirth; G. Davies; S. Matthews; M. B. Shortt; A. Rees; A. Mir; A. Henderson; R. J. Prescott; P. de Feyter



Human serum paraoxonase (PON 1) is inactivated by oxidized low density lipoprotein and preserved by antioxidants  

Microsoft Academic Search

Human serum paraoxonase (PON1) can protect low density lipoprotein (LDL) from oxidation induced by either copper ion or by the free radical generator azo bis amidinopropane hydrochloride (AAPH). During LDL oxidation in both of these systems, a time-dependent inactivation of PON arylesterase activity was observed. Oxidized LDL (Ox-LDL) produced by lipoprotein incubation with either copper ion or with AAPH, indeed

Michael Aviram; Mira Rosenblat; Scott Billecke; John Erogul; Robert Sorenson; Charles L Bisgaier; Roger S Newton; Bert La Du



One precursor, three apolipoproteins: the relationship between two crustacean lipoproteins, the large discoidal lipoprotein and the high density lipoprotein/?-glucan binding protein.  


The novel discoidal lipoprotein (dLp) recently detected in the crayfish, differs from other crustacean lipoproteins in its large size, apoprotein composition and high lipid binding capacity, We identified the dLp sequence by transcriptome analyses of the hepatopancreas and mass spectrometry. Further de novo assembly of the NGS data followed by BLAST searches using the sequence of the high density lipoprotein/1-glucan binding protein (HDL-BGBP) of Astacus leptodactylus as query revealed a putative precursor molecule with an open reading frame of 14.7 kb and a deduced primary structure of 4889 amino acids. The presence of an N-terminal lipid bind- ing domain and a DUF 1943 domain suggests the relationship with the large lipid transfer proteins. Two-putative dibasic furin cleavage sites were identified bordering the sequence of the HDL-BGBP. When subjected to mass spectroscopic analyses, tryptic peptides of the large apoprotein of dLp matched the N-terminal part of the precursor, while the peptides obtained for its small apoprotein matched the C-terminal part. Repeating the analysis in the prawn Macrobrachium rosenbergii revealed a similar protein with identical domain architecture suggesting that our findings do not represent an isolated instance. Our results indicate that the above three apolipoproteins (i.e HDL-BGBP and both the large and the small subunit of dLp) are translated as a large precursor. Cleavage at the furin type sites releases two subunits forming a heterodimeric dLP particle, while the remaining part forms an HDL-BGBP whose relationship with other lipoproteins as well as specific functions are yet to be elucidated. PMID:25281909

Stieb, Stefanie; Roth, Ziv; Dal Magro, Christina; Fischer, Sabine; Butz, Eric; Sagi, Amir; Khalaila, Isam; Lieb, Bernhard; Schenk, Sven; Hoeger, Ulrich



Very low density lipoproteins stimulate surfactant lipid synthesis in vitro.  

PubMed Central

Surfactant synthesis is critically dependent on the availability of fatty acids. One fatty acid source may be circulating triglycerides that are transported in VLDL, and hydrolyzed to free fatty acids by lipoprotein lipase (LPL). To evaluate this hypothesis, we incubated immortalized or primary rat alveolar pre-type II epithelial cells with VLDL. The cells were observed to surface bind, internalize, and degrade VLDL, a process that was induced by exogenous LPL. LPL induction of lipoprotein uptake significantly increased the rates of choline incorporation into phosphatidylcholine (PC) and disaturated PC, and these effects were associated with a three-fold increase in the activity of the rate-regulatory enzyme for PC synthesis, cytidylyltransferase. Compared with native LPL, a fusion protein of glutathione S-transferase with the catalytically inactive carboxy-terminal domain of LPL did not activate CT despite inducing VLDL uptake. A variant of the fusion protein of glutathione S-transferase with the catalytically inactive carboxy-terminal domain of LPL that partially blocked LPL-induced catabolism of VLDL via LDL receptors also partially blocked the induction of surfactant synthesis by VLDL. Taken together, these observations suggest that both the lipolytic actions of LPL and LPL-induced VLDL catabolism via lipoprotein receptors might play an integral role in providing the fatty acid substrates used in surfactant phospholipid synthesis. PMID:9109447

Mallampalli, R K; Salome, R G; Bowen, S L; Chappell, D A



Distribution and Kinetics of Lipoprotein-Bound Endotoxin  

PubMed Central

Lipopolysaccharide (LPS), the major glycolipid component of gram-negative bacterial outer membranes, is a potent endotoxin responsible for pathophysiological symptoms characteristic of infection. The observation that the majority of LPS is found in association with plasma lipoproteins has prompted the suggestion that sequestering of LPS by lipid particles may form an integral part of a humoral detoxification mechanism. Previous studies on the biological properties of isolated lipoproteins used differential ultracentrifugation to separate the major subclasses. To preserve the integrity of the lipoproteins, we have analyzed the LPS distribution, specificity, binding capacity, and kinetics of binding to lipoproteins in human whole blood or plasma by using high-performance gel permeation chromatography and fluorescent LPS of three different chemotypes. The average distribution of O111:B4, J5, or Re595 LPS in whole blood from 10 human volunteers was 60% (±8%) high-density lipoprotein (HDL), 25% (±7%) low-density lipoprotein, and 12% (±5%) very low density lipoprotein. The saturation capacity of lipoproteins for all three LPS chemotypes was in excess of 200 ?g/ml. Kinetic analysis however, revealed a strict chemotype dependence. The binding of Re595 or J5 LPS was essentially complete within 10 min, and subsequent redistribution among the lipoprotein subclasses occurred to attain similar distributions as O111:B4 LPS at 40 min. We conclude that under simulated physiological conditions, the binding of LPS to lipoproteins is highly specific, HDL has the highest binding capacity for LPS, the saturation capacity of lipoproteins for endotoxin far exceeds the LPS concentrations measured in clinical situations, and the kinetics of LPS association with lipoproteins display chemotype-dependent differences. PMID:11292694

Levels, J. H. M.; Abraham, P. R.; van den Ende, A.; van Deventer, S. J. H.



Protein interactions among Fe65, the low-density lipoprotein receptor-related protein, and the amyloid precursor protein.  


The adapter protein Fe65 has been proposed to be the link between the intracellular domains of the amyloid precursor protein, APP (AICD), and the low-density lipoprotein receptor-related protein (LRP-CT). Functional linkage between these two proteins has been established, and mutations within LRP-CT affect the amount of A? produced from APP. Previous work showed that AICD binds to protein interaction domain 2 (PID2) of Fe65. Although the structure of PID1 was determined recently, all attempts to demonstrate LRP-CT binding to this domain failed. We used biophysical experiments and binding studies to investigate the binding among these three proteins. Full-length Fe65 bound more weakly to AICD than did N-terminally truncated forms; however, the intramolecular domain-domain interactions that had been proposed to inhibit binding could not be observed using amide H-D exchange. Surprisingly, when LRP-CT is phosphorylated at Tyr4507, it bound to Fe65 PID1 despite the fact that this domain belongs to the Dab-like subclass of PIDs that are not supposed to be phosphorylation-dependent. Mutation of a critical arginine abolished binding, providing further proof of the phosphorylation dependence. Fe65 PID1 thus provides a link between the Dab-like class and the IRS-like class of PIDs and is the first Dab-like family member to show phosphorylation-dependent binding. PMID:21650223

Mulvihill, Melinda M; Guttman, Miklos; Komives, Elizabeth A



Low density lipoprotein-induced growth of U937 cells: a novel method to determine the receptor binding of low density lipoprotein  

Microsoft Academic Search

U937 is a monocytic cell-line originally derived from a histiocytic lymphoma. In serum-free medium the growth of U937 cells was stimulated by addition of low density lipoprotein (LDL). Methylation of LDL impaired its ability to be taken up in U937 cells as well as the capacity to stimulate the growth of these cells. Pretreatment of U937 cells with a monoclonal

Johan Frostegird; Anders Hamsten; Magnus Gidlund; Jan Nilsson


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



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

Technology Transfer Automated Retrieval System (TEKTRAN)

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



Technology Transfer Automated Retrieval System (TEKTRAN)

The purpose of this review is to summarize the current understanding of the potentially anti-atherogenic properties of high-density lipoprotein related to its different components. Recent findings on the role of the different high-density lipoprotein subspecies in reverse cholesterol transport, infl...


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


Particulate Matter Promotes In Vitro Receptor-Recognizable Low-Density Lipoprotein Oxidation and Dysfunction of Lipid Receptors  

PubMed Central

Particulate matter may promote cardiovascular disease, possibly as a consequence of its oxidative potential. Studies using susceptible animals indicate that particulate matter aggravates atherosclerosis by increasing lipid/macrophage content in plaques. Macrophage lipid uptake requires oxidized low-density lipoprotein and scavenger receptors; same receptors are involved in particulate matter uptake. We studied in vitro particulate matter potential to oxidize low-density lipoproteins and subsequent cell uptake through scavenger receptors. Particulate matter-induced low-density lipoproteins oxidation was evaluated by the thiobarbituric acid assay. Binding/internalization was tested in wild type and scavenger receptor–transfected Chinese hamster ovary cells, and in RAW264.7 cells using fluorescently labeled low-density lipoproteins. Dose-dependent binding/internalization only occurred in scavenger receptor–transfected Chinese hamster ovary cells and RAW264.7 cells. Competition binding/internalization using particles showed that particulate matter induced decreased binding (~50%) and internalization (~70%) of particle-oxidized low-density lipoproteins and native low-density lipoproteins. Results indicate that particulate matter was capable of oxidizing low-density lipoproteins, favoring macrophage internalization, and also altered scavenger and low-density lipoproteins receptor function. PMID:23297186

Manzano-León, Natalia; Mas-Oliva, Jaime; Sevilla-Tapia, Laura; Morales-Bárcenas, Rocío; Serrano, Jesús; O’Neill, Marie S.; García-Cuellar, Claudia M.; Quintana, Raúl; Vázquez-López, Inés



The Catalytic Histidine Dyad of High Density Lipoprotein-associated Serum Paraoxonase-1 (PON1) Is Essential for  

E-print Network

The Catalytic Histidine Dyad of High Density Lipoprotein- associated Serum Paraoxonase-1 (PON1) Is Essential for PON1-mediated Inhibition of Low Density Lipoprotein Oxidation and Stimulation of Macrophage)-associated paraoxonase-1 (PON1) anti-atherogenic properties in macrophages, i.e. inhibition of cell-mediated oxidation

Tawfik, Dan S.


Stimulated arachidonate metabolism during foam cell transformation of mouse peritoneal macrophages with oxidized low density lipoprotein.  

PubMed Central

Changes in arachidonate metabolism were examined in mouse peritoneal macrophages incubated with various types of lipoproteins. Oxidized low density lipoprotein (LDL) was incorporated by macrophages and stimulated macrophage prostaglandin E2 (PGE2) and leukotriene C4 syntheses, respectively, 10.8- and 10.7-fold higher than by the control. Production of 6-keto-PGF1 alpha, a stable metabolite of prostacyclin, was also stimulated. No stimulation was found with native LDL, which was minimally incorporated by the cells. Acetylated LDL and beta-migrating very low density lipoprotein (beta-VLDL), though incorporated more efficiently than oxidized LDL, also had no stimulatory effect. When oxidized LDL was separated into the lipoprotein-lipid peroxide complex and free lipid peroxides, most of the stimulatory activity was found in the former fraction, indicating that stimulation of arachidonate metabolism in the cell is associated with uptake of the lipoprotein-lipid peroxide complex. These results suggest that peroxidative modification of LDL could contribute to the progression of atheroma by stimulating arachidonate metabolism during incorporation into macrophages. Images PMID:3125226

Yokode, M; Kita, T; Kikawa, Y; Ogorochi, T; Narumiya, S; Kawai, C



Indication of low-density lipoprotein apheresis in severe hypercholesterolemia and its atherosclerotic vascular complications: dextran sulfate cellulose low-density lipoprotein apheresis.  


Homozygous familial hypercholesterolemia (FH) and heterozygous FH, with or without elevation of Lp(a), or isolated massive elevation of Lp(a) with clinically relevant coronary heart disease are indications for low-density lipoprotein (LDL) apheresis, as long as maximal conventional lipid lowering drug therapy does not lead to a LDL cholesterol level below 100 mg/dL. Reduction of lipoproteins and Lp(a), of oxidation of LDL, improvement of disturbed vasomotion, the procoagulatory state and disturbed hemorheology associated with atherosclerosis, as well as the stabilization of plaques and the decrease of cytokines and adhesion molecules have been induced by apheresis and are thought to favorably influence regression of artherosclerosis. Several intervention studies point in this direction. PMID:12924611

Keller, Christiane



Interconversion of high density lipoproteins during incubation of human plasma  

SciTech Connect

Incubation (6h,37/sup 0/) of untreated human plasma resulted in marked reductions in concentrations of two major subpopulations (mean sizes: approx.84 angstroms and approx.79 angstroms) of the HDL/sub 3/ subclass. These reductions were accompanied by the appearance of large species with mean particle size (95.2 angstroms) in the range of the HDL/sub 2a/ subpopulations. In the presence of mercaptoethanol (14 mM), incubation resulted in further reduction of the two HDL/sub 3/ subpopulations but now with formation of both larger (95.4 angstroms) and smaller (77.2 and 75.2 angstroms) species. Inhibitors of lecithin:cholesterol acyltransferase showed varying effectivenss in modifying the extent and character of the interconversion. With paraoxon (2 mM) the interconversion was much reduced and was associated with the formation predominantly of smaller particles (74.6 angstroms); with 5,5'-dithiobis-(2-nitrobenzoic acid) (1.4 mM) the interconversion resembled that produced with mecaptoethanol but to a considerably lesser degree. Incubation of HDL, ultracentrifugally isolated from nonincubated plasma containing paraoxon, resulted in negligible interconversion, suggesting that other plasma components participate in the process.

Nichols, A.V.; Gong, E.L.; Blanche, P.J.



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

E-print Network

of the present study was to develop a rapid method for the separation, purification, density measurement, and characterization of Lp(a) from serum using a procedure that is isoform independent. The objective was met by linking ultracentrifugation with affinity...

Espinosa Garcia, Irma Leticia



Mutant Oocytic Low Density Lipoprotein Receptor Gene Family Member Causes Atherosclerosis and Female Sterility  

Microsoft Academic Search

The so-called very low density lipoprotein receptors (VLDLRs) are related to the LDLR gene family. So far, naturally occurring mutations have only been described for the prototype LDLR; in humans, they cause familial hypercholesterolemia. Here we describe a naturally occurring mutation in a VLDLR that causes a dramatic abnormal phenotype. Hens of the mutant restricted-ovulator chicken strain carry a single

Hideaki Bujo; Tokuo Yamamoto; Kozo Hayashi; Marcela Hermann; Johannes Nimpf; Wolfgang Johann Schneider



Direct Low Density Lipoprotein Cholesterol and Glycated Albumin Levels in Type 2 Diabetes Mellitus  

Technology Transfer Automated Retrieval System (TEKTRAN)

Diabetes mellitus is a major risk factor for coronary heart disease (CHD), renal failure, retinopathy, and neuropathy. Lowering glycosylated hemoglobin (HbA1c) as well as low-density lipoprotein-cholesterol (LDL-C) have been associated with a decreased risk of these complications. The aim in this st...



Technology Transfer Automated Retrieval System (TEKTRAN)

An elevated low density lipoprotein cholesterol (LDL-C) level is an independent risk factor for premature coronary heart disease (CHD), with a value of $160 mg/dL designated as high-risk by the National Cholesterol Education Program Adult Treatment Panels I and II. Goals of therapy for all patients...


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

E-print Network

Scavenger Receptor Class B Type I Protein as an Independent Predictor of High-Density Lipoprotein, Kentucky 40507 Context: In mice, scavenger receptor class B, type I (SR-BI) receptor protein deficiency, is the scavenger re- ceptor, class B, type I (SR-BI) receptor. SR-BI was isolated and characterized

Terasaki, Mark


Macrophage Oxidation of Low Density Lipoprotein Generates a Modified Form Recognized by the Scavenger Receptor  

Microsoft Academic Search

Incubation of low density lipoprotein (LDL) with endothelial cells or smooth muscle cells overnight has resulted in an oxtdative modification of LDL that results in its recognition by macrophages by way of the acetyl LDL receptor. In the present study, we examined whether macrophages themselves can oxidize and modify LDL in a manner similar to that of endothelial cells. Incubation

Sampath Parthasarathy; David J. Printz; Donna Boyd; Lorna Joy; Daniel Steinberg



Exchange of phospholipids between low and high density lipoproteins of squirrel monkeys  

Microsoft Academic Search

Ultracentrifugal analysis of the plasma of squirrel monkeys at various times after the injection of (Me-14C)choline revealed the specific activities of lecithin in both high (HDL) and low (LDL) density lipoproteins to be similar. This was also true for sphingomyelin. The exchange of phospholipids in vitro was studied by incubating unlabeled plasma with labeled LDL and HDL iso- lated 40

D. Roger Illingworth; Oscar W. Portman



Hepatitis C Virus and other Flaviviridae Viruses Enter Cells via Low Density Lipoprotein Receptor  

Microsoft Academic Search

Endocytosis of the Flaviviridae viruses, hepatitis C virus, GB virus C\\/hepatitis G virus, and bovine viral diarrheal virus (BVDV) was shown to be mediated by low density lipoprotein (LDL) receptors on cultured cells by several lines of evidence: by the demonstration that endocytosis of these virus correlated with LDL receptor activity, by complete inhibition of detectable endocytosis by anti-LDL receptor

Vincent Agnello; Gyorgy Abel; Mutasim Elfahal; Glenn B. Knight; Qing-Xiu Zhang



High Density Lipoprotein Cholesterol and the Risk of Stroke in Elderly Men: The Honolulu Heart Program  

Microsoft Academic Search

High density lipoprotein (HDL) cholesterol has been inversely associated with coronary heart disease. Associations with stroke are less clear, particularly among the elderly. In this study, the authors examined the relation between HDL cholesterol levels and the risk of stroke in elderly men. Levels of HDL cholesterol were measured in 2,444 Honolulu Heart Program men aged 71-93 years at the

J. David Curb; Robert D. Abbott; Beatriz L. Rodriguez; Kamal H. Masaki; Randi Chen; Jordan S. Popper; Helen Petrovitch; G. Webster Ross; Irwin J. Schatz; Gina C. Belleau; Katsuhiko Yano




Technology Transfer Automated Retrieval System (TEKTRAN)

High levels of small low-density lipoprotein (LDL) particles are a major risk factor for cardiovascular morbidity and mortality. Both estrogens and smoking, with known anti-estrogenic effects, alter the atherogenic lipid profile. We tested for a role of interaction between smoking and estrogen recep...


Phospholipid transfer protein enhances removal of cellular cholesterol and phospholipids by high-density lipoprotein apolipoproteins  

Microsoft Academic Search

High-density lipoprotein (HDL) apolipoproteins remove excess cholesterol from cells by an active transport pathway that may protect against atherosclerosis. Here we show that treatment of cholesterol-loaded human skin fibroblasts with phospholipid transfer protein (PLTP) increased HDL binding to cells and enhanced cholesterol and phospholipid efflux by this pathway. PLTP did not stimulate lipid efflux in the presence of albumin, purified

Gertrud Wolfbauer; John J Albers; John F Oram



Glycated albumin and direct low density lipoprotein cholesterol levels in type 2 diabetes mellitus  

Technology Transfer Automated Retrieval System (TEKTRAN)

Diabetes mellitus is a major risk factor for coronary heart disease (CHD), renal failure, retinopathy, and neuropathy. Lowering glycosylated hemoglobin (HbA1c) as well as low-density lipoprotein-cholesterol (LDL-C) has been associated with a decreased risk of these complications. We evaluated the ut...


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

PubMed Central

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

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



Psoriasis decreases the anti-oxidation and anti-inflammation properties of high-density lipoprotein.  


Psoriasis is a chronic inflammatory skin disease, which has been linked to dyslipidemia with potential functional impairment of lipoproteins. This cross-sectional study was designed to characterize the biological activities of plasma lipoproteins in 25 patients with psoriasis and 25 age- and sex-matched healthy controls. In the present study, we found that plasma levels of high-density lipoprotein (HDL) cholesterol were decreased in the psoriasis group compared to healthy controls. The malondialdehyde (MDA) content in plasma, in HDL3 and in low-density lipoprotein (LDL) were increased. However, the activity of plasma paraoxonase-1 (PON-1) decreased in psoriasis and negatively correlated with the psoriasis area and severity index (PASI). Moreover, plasma levels of tumor necrosis factor-? (TNF-?) and interleukin-6 (IL-6) were increased in psoriasis and positively correlated with the PASI. High-sensitivity C-reactive protein (hs-CRP) was increased in psoriasis, but did not reach significance when correlated with PASI. In vitro tests displayed that the functionalities of HDL3 isolated from psoriatic patients significantly decreased, which were assessed in four independent ways, namely (1) protection against LDL oxidation, (2) inhibition of tumor necrosis factor-? (TNF-?) induced monocyte adherence to endothelial cells, (3) prevention of oxidized low density lipoprotein (ox-LDL) induced monocyte migration, and (4) protection of endothelial cells from TNF-? induced apoptosis. Further, pro-oxidative and pro-inflammatory properties of LDL isolated from psoriatic patients were increased. In conclusion, the biological activities of psoriatic lipoproteins are impaired in both HDL and LDL which may provide a link between psoriasis and cardiovas- cular disease. PMID:25240836

He, Lei; Qin, Shucun; Dang, Lin; Song, Guohua; Yao, Shutong; Yang, Nana; Li, Yuzhen



Function and significance of very low density lipoprotein receptor subtype II  

Microsoft Academic Search

Summary  To explore the functions of very low density lipoprotein receptor (VLDL-R) subtype II in lipoprotein metabolism and foam cells\\u000a formation, the recombinant plasmid with the two subtypes cDNA was constructed respectively, the ldl-A7 cell lines were transfected\\u000a and two cell lines expressing VLDL-R were obtained: one stably expressing the VLDLR with the O-linked sugar region (type I\\u000a VLDLR) and the

Tian Jun; Bi Hao; Li Yinghong; Yang Pu; Zong Yiqiang; Wang Yu; Qu Shen



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

PubMed Central

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 co-receptor 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 re-investigated the ligand concentration dependence of 125I-HDL binding to SR-BI and SR-BI-mediated specific uptake of [3H]CE from [3H]CE-HDL using an expanded range of ligand concentrations (<1 µg protein/ml, lower than previously reported). Scatchard and non-linear 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 125I-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



Effects of sex on formation and properties of plasma very low density lipoprotein in vivo  

Microsoft Academic Search

The concentration and composition of the very low density lipoprotein (VLDL) lipids and the behavior of the VLDL in a density\\u000a gradient in the zonal ultracentrifuge were examined in plasma obtained from normal fed male and female rats before and after\\u000a intravenous injection of Triton WR-1339. Concentration of lipids in plasma VLDL of female rats was about half that of

Carlos Soler-Argilaga; Abraham Danon; Henry G. Wilcox; Murray Heimberg



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



Assembly of very low density lipoproteins in mouse liver: evidence of heterogeneity of particle density in the Golgi apparatus.  


The assembly of very low density lipoproteins (VLDL) by hepatocytes is believed to occur via a two-step process. The first step is the formation of a dense phospholipid and protein-rich particle that is believed to be converted to VLDL by the addition of bulk triglyceride in a second step. Previous studies in our laboratory led us to hypothesize a third assembly step that occurs in route to or in the Golgi apparatus. To investigate this hypothesis, nascent lipoproteins were recovered from Golgi apparatus-rich fractions isolated from mouse liver. The Golgi fractions were enriched 125-fold in galactosyltransferase and contained lipoprotein particles averaging approximately 35 nm in diameter. These lipoproteins were separated by ultracentrifugation into two fractions: d < 1.006 g/ml and d1.006;-1.210 g/ml. The d < 1.006 g/ml fraction contained apolipoprotein B-100 (apoB-100), apoB-48, and apoE, while the d1.006;-1.210 g/ml fraction contained these three apoproteins as well as apoA-I and apoA-IV. Both fractions contained a 21-kDa protein that was isolated and sequenced and identified as major urinary protein. Approximately 50% of the apoB was recovered with the denser fraction. To determine if these small, dense lipoproteins were secreted without further addition of lipid, mice were injected with Triton WR1339 and [(3)H]leucine, and the secretion of apoB-100 and apoB-48 into serum VLDL (d < 1.006 g/ml) and d1.006;-1.210 g/ml fractions was monitored over a 2-h period. More than 80% of the newly synthesized apoB-48 and nearly 100% of the apoB-100 were secreted with VLDL. These studies provide the first characterization of nascent lipoproteins recovered from the Golgi apparatus of mouse liver. We conclude that these nascent hepatic Golgi lipoproteins represent a heterogeneous population of particles including VLDL as well as a population of small, dense lipoproteins. The finding of the latter particles, coupled with the demonstration that the primary secretory product of mouse liver is VLDL, suggests that lipid may be added to nascent lipoproteins within the Golgi apparatus. PMID:11181751

Swift, L L; Valyi-Nagy, K; Rowland, C; Harris, C



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



Apolipoprotein E on Hepatitis C Virion Facilitates Infection through Interaction with Low Density Lipoprotein Receptor  

PubMed Central

Hepatitis C virus (HCV) infection is a major cause of liver disease. HCV associates with host apolipoproteins and enters hepatocytes through complex processes involving some combination of CD81, claudin-I, occludin, and scavenger receptor BI. Here we show that infectious HCV resembles very low density lipoprotein (VLDL) and that entry involves co-receptor function of the low density lipoprotein receptor (LDL-R). Blocking experiments demonstrate that ?-VLDL itself or anti-apolipoprotein E (apoE) antibody can block HCV entry. Knockdown of the LDL-R by treatment with 25-hydroxycholesterol or siRNA ablated ligand uptake and reduced HCV infection of cells, whereas infection was rescued upon cell ectopic LDL-R expression. Analyses of gradient-fractionated HCV demonstrate that apoE is associated with HCV virions exhibiting peak infectivity and dependence upon the LDL-R for cell entry. Our results define the LDL-R as a cooperative HCV co-receptor that supports viral entry and infectivity through interaction with apoE ligand present in an infectious HCV/lipoprotein complex comprising the virion. Disruption of HCV/LDL-R interactions by altering lipoprotein metabolism may therefore represent a focus for future therapy. PMID:19751943

Owen, David M.; Huang, Hua; Ye, Jin; Gale, Michael




Technology Transfer Automated Retrieval System (TEKTRAN)

High-density lipoprotein (HDL) is a heterogeneous lipoprotein class and there is no consensus on the value of HDL subspecies in coronary heart disease (CHD) risk assessment. We tested the hypothesis whether specific HDL subpopulations are significantly associated with CHD-prevalence. ApoA-I concentr...


Comparative long-term experience with immunoadsorption and dextran sulfate cellulose adsorption for extracorporeal elimination of low-density lipoproteins  

Microsoft Academic Search

Two low-density lipoprotein (LDL) apheresis methods allowing a specific extracorporeal removal of atherogenic lipoproteins from plasma were compared concerning their efficacy and safety in the long-term therapy of severe familial hypercholesterolemia. Five patients were treated with immunoadsorption (IMA) at weekly intervals over 3 years each, and three patients received weekly therapy with dextran sulfate cellulose adsorption (DSA) for up to

W. Knisel; M. Pfohl; M. Müller; I. Besenthal; A. Nicuolo; W. Voelker; T. Risler; M. Eggstein



Enzymatic modification of low density lipoprotein by purified lipoxygenase plus phospholipase AP mimics cell-mediated oxidative modification  

Microsoft Academic Search

Low density lipoprotein (LDL) can be oxidatively modified by cultured endothelial cells or by cupric ions, resulting in increased macrophage uptake of the lipoprotein. This process could be relevant to the formation of macrophage-derived foam cells in the early atherosclerotic lesion. The mechanism of endo- thelial cell modification of LDL is unknown. In the present work we show that incubation

Carl P. Sparrow; Sampath Parthasarathy; Daniel Steinberg


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)



Low density lipoprotein fraction assay for cardiac disease risk  


A variable rate density gradient electrophoric gel is described which separates LDL subfractions with the precision of ultracentrifugation techniques. Also, an innovative bottom inlet mixing chamber particularly useful for producing these gels is described. 8 figs.

Krauss, R.M.; Blanche, P.J.; Orr, J.



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.  


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

Boden, W E



Reduction of low-density lipoproteins with dextran sulfate in patients with familial hypercholesterolemia.  


A novel on-line system for the selective precipitation of low-density lipoprotein (LDL) using dextran sulfate has been devised and tested in four patients with heterozygous familial hypercholesterolemia (type II). The mean pretreatment serum cholesterol was 410 mg/dl. Plasma was generated by membrane filtration and LDL and VLDL (very-low-density lipoprotein) were completely precipitated with 10-35 mg% dextran sulfate (Mr 5,000) in the presence of 55 mM Ca2+. The precipitate was removed by filtration and the excess Ca2+ by dialysis. For 41 procedures the mean reduction of plasma solutes was LDL + VLDL 65%, HDL 23%, fibrinogen 19%, albumin 15%, IgG 20%, IgA 19%, IgM 24%. We conclude that dextran sulfate precipitation is an effective method for selective on-line removal of LDL from plasma. PMID:2455708

Antwiler, G D; Dau, P C; Lobdell, D D



Clearance of coagulation factor VIII in very low-density lipoprotein receptor knockout mice.  


Low-density lipoprotein receptor-related protein (LRP) contributes to factor VIII (FVIII) catabolism in vivo. Besides LRP, FVIII also interacts with very low-density lipoprotein receptor (VLDLR) in vitro. We investigated the physiological role of VLDLR in FVIII catabolism, using knockout mouse models for VLDLR and LRP, alone and in combination. VLDLR(-/-) mice displayed normal plasma FVIII, whereas VLDLR(-/-) LRP(-) double-knockout mice had slightly increased FVIII compared with LRP-deficient mice. Remarkably, VLDLR deficiency slightly accelerated FVIII clearance. Adenovirus-mediated overexpression of VLDLR did not lower plasma FVIII in LRP-deficient mice. We conclude that VLDLR does not act in concert with LRP in FVIII clearance in vivo. PMID:15327526

Bovenschen, Niels; van Dijk, Ko Willems; Havekes, Louis M; Mertens, Koen; van Vlijmen, Bart J M



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


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



Oxidized low-density lipoprotein-binding specificity of Asp-hemolysin from Aspergillus fumigatus  

Microsoft Academic Search

Oxidized low-density lipoprotein (Ox-LDL) is known to be involved in the generation and progression of atherosclerosis. Ox-LDL has a number of potentially atherogenic effects on vascular cells, including the uncontrolled uptake by scavenger receptors. We have previously shown that Asp-hemolysin binds to Ox-LDL in a concentration-dependent manner. The present study was undertaken to clarify the binding specificity of Asp-hemolysin to

Yoichi Kudo; Yuji Fukuchi; Takeshi Kumagai; Keiichi Ebina; Katsushi Yokota



Particle size analysis of high density lipoproteins in patients with genetic cholesteryl ester transfer protein deficiency  

Microsoft Academic Search

We investigated the detailed distribution of high-density lipoproteins (HDL) particle size in patients with cholesteryl ester transfer protein (CETP) deficiency. Serum samples pre-stained with Sudan black B were electrophoresed using 4–30% polyacrylamide gradient gels, and the Stokes diameter of HDL particles was determined in 23 patients with genetic CETP deficiency, nine patients with hyperalphalipoproteinemia and seven subjects with normal HDL

Tomoko Arai; Toshihiko Tsukada; Toshio Murase; Kojiro Matsumoto



Oxidized Low-Density Lipoprotein and Oxidative Stress in the Development of Glomerulosclerosis  

Microsoft Academic Search

Glomerulosclerosis frequently complicates most renal diseases and is characterized by mesangial matrix accumulation. Oxidized low-density lipoprotein (Ox-LDL) could induce oxidative stress and profibrotic gene expression in mesangial cells. This article will review our current understanding of the pathogenetic mechanisms of lipid-mediated glomerulosclerosis, emphasizing the fibrogenic signaling cascades triggered by Ox-LDL. In addition, therapeutic strategies to prevent the development of Ox-LDL-mediated

Hyun Soon Lee; Chi Young Song



Effect of Cocoa Bran on Low-Density Lipoprotein Oxidation and Fecal Bulking  

Microsoft Academic Search

Background: Legumes have reported benefits in terms of reduced risk for coronary heart disease and of colonic health. A novel legume fiber, cocoa bran, also may have favorable health effects on serum lipid levels, low- density lipoprotein (LDL) cholesterol oxidation, and fe- cal bulk. Methods: Twenty-five healthy normolipidemic sub- jects (13 men and 12 women) (mean±SEM age, 37±2 years; mean

David J. A. Jenkins; Cyril W. C. Kendall; Vladimir Vuksan; Edward Vidgen; Evelyn Wong; Livia S. A. Augustin; Victor Fulgoni



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


Oxidized low-density lipoprotein induces the production of interleukin-8 by endothelial cells  

Microsoft Academic Search

The concentration of interleukin-8 (IL-8) and RANTES was measured in culture supernatants of human EA.hy 926 endothelial cells incubated with oxidized low-density lipoproteins (LDL). Oxidized LDL induced a 3-fold increase in IL-8 production (p < 0.01), whereas RANTES was not detected. Native LDL did not stimulate IL-8 production. IL-8 production in oxidized-LDL-treated cells was mediated by reactive oxygen species, as

Catherine Claise; Marvin Edeas; Jacqueline Chalas; Anélie Cockx; Annie Abella; Liliane Capel; Albert Lindenbaum



Effect of ethyl esterification of phenolic acids on low-density lipoprotein oxidation  

Microsoft Academic Search

Inhibition of copper-induced low-density lipoprotein (LDL) oxidation by phenolic acids and their ethyl esters was investigated. LDL oxidation was evaluated by the hydroperoxide concentration and the chromatographic pattern of apoprotein fractions after fast protein liquid chromatography (FPLC). Antiradical properties against 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical and 2,2’-azobis(2-amidinopropane)dihydrochloride (AAPH) were also investigated, and lipophilicity determined by thin-layer chromatography.Caffeic acid at 5 ?M and

J. Chalas; C. Claise; M. Edeas; C. Messaoudi; L. Vergnes; A. Abella; A. Lindenbaum



Inhibition of in vitro macrophage-induced low density lipoprotein oxidation by thyroid compounds  

Microsoft Academic Search

Oxidized low density lipoproteins (LDL) are highly sus- pected of initiating the atherosclerosis process. Thyroid hormones and structural analogues have been reported to protect LDL from lipid peroxidation induced by Cu2+ or the free radical generator 2,2-azobis-(2-amidinopropane) dihydrochloride in vitro. We have examined the effects of thyroid compounds on macrophage-induced LDL oxidation. Human monocyte-derived macrophages (dif- ferentiated U937 cells) were

L Oziol; P Faure; N Bertrand; P Chomard



Pharmaceutical Nanotechnology Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme  

Microsoft Academic Search

The low density lipoprotein (LDL) receptor has been shown to be upregulated in GBM tumor cells and is therefore a potential molecular target for the delivery of therapeutic agents. A synthetic nano-LDL (nLDL) particle was developed and tested to determine its utility as a drug delivery vehicle targeted to GBM tumors. nLDL particles were constructed by combining a synthetic peptide

Mina Nikanjam; Eleanor A. Blakely; Kathleen A. Bjornstad; Xiao Shu; Thomas F. Budinger; Trudy M. Forte


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



Age-dependent associations of smoking and drinking with non–high-density lipoprotein cholesterol  

Microsoft Academic Search

Serum high-density lipoprotein (HDL) cholesterol levels are influenced by habitual smoking and drinking. Non-HDL cholesterol is known to be a potent predictor of cardiovascular disease. However, it remains to be determined whether the associations of non-HDL cholesterol with smoking and drinking differ with age. The objectives of this study were to investigate relationships among smoking, drinking, and non-HDL cholesterol and

Ichiro Wakabayashi; Klaus Groschner



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



Antioxidants decreases the intensification of low density lipoprotein in vivo peroxidation during therapy with statins  

Microsoft Academic Search

The oxidative modification of low density lipoprotein (LDL) is thought to play an important role in atherogenesis. Drugs of ß-hydroxy-ß-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) family are usually used as a very effective lipid-lowering preparations but they simultaneously block biosynthesis of both cholesterol and ubiquinone Q10 (coenzyme Q), which is an intermediate electron carrier in the mitochondrial respiratory chain.

Vadim Z. Lankin; Alla K. Tikhaze; Valery V. Kukharchuk; Galina G. Konovalova; Oleg I. Pisarenko; Alexander I. Kaminnyi; Konstantin B. Shumaev; Yury N. Belenkov



Regulation of hepatic secretion of very low density lipoprotein by dietary cholesterol  

Microsoft Academic Search

Male rats were fed a cholesterol-free diet or the same diet supplemented with either 0.05, 0.1, 0.25, 0.5, 1, or 2% C for 21 days to investigate the effects of cholesterol on secretion of very low density lipoprotein (VLDL). Cholester- ol feeding increased plasma and hepatic concentrations of triglyceride (TG) and cholesteryl esters (CE) in a dosede- pendent manner. Plasma

Thomas V. Fungwe; Lauren Cagen; Henry G. Wdcox; Murray Heimberg


Oxidized low density lipoprotein stimulates collagen production in cultured arterial smooth muscle cells  

Microsoft Academic Search

We examined the interactive effect of oxidized low density lipoprotein (LDL) and ascorbic acid on collagen production in cultured smooth muscle cells (SMCs). Porcine aortic SMCs were incubated with 50–200 ?g\\/ml of human LDL with\\/without 5 ?M Cu2+ for 24 h. Collagen production was assayed by successive salt precipitation at acidic and neutral pH after pepsin digestion of 3H-proline-labeled collagenous

Shiro Jimi; Keijiro Saku; Noriko Uesugi; Noriyuki Sakata; Shigeo Takebayashi



Molecular mechanism of low density lipoprotein oxidation by 12-lipoxygenase-overexpressing macrophages  

Microsoft Academic Search

Oxidative modification of low-density lipoprotein (LDL) leads to foam cell formation in atherosclerosis. The involvement of 12- and 15-lipoxygenases in LDL oxidation has been implicated by enzymological and knockout mouse studies. However, the molecular basis of oxidized LDL formation in vivo has not yet been elucidated. We constructed expression vectors pEF-BOS for porcine leukocyte and human platelet 12-lipoxygenases exhibiting distinct

Tanihiro Yoshimoto; Yoshitaka Takahashi; Wanpeng Xu; Takahiro Kinoshita; Toshiki Sakashita; Hiroshi Mabuchi



Effect of rosuvastatin on low-density lipoprotein cholesterol in patients with hypercholesterolemia  

Microsoft Academic Search

Rosuvastatin is a new, synthetic, orally active statin, with marked low-density lipoprotein (LDL) cholesterol-lowering activity. We conducted 2 dose-ranging studies. In the first study, after a 6-week dietary run-in, 142 moderately hypercholesterolemic patients were randomized equally to receive double-blind placebo or rosuvastatin 1, 2.5, 5, 10, 20, or 40 mg or open-label atorvastatin 10 or 80 mg once daily for

Anders G Olsson; John Pears; John McKellar; Jacques Mizan; Ali Raza



Autoantibodies to low-density-lipoprotein-receptor-related protein 2 (LRP2) in systemic autoimmune diseases  

Microsoft Academic Search

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

Seido Ooka; Toshihiro Matsui; Kusuki Nishioka; Tomohiro Kato



Effects of atorvastatin treatment on the oxidatively modified low density lipoprotein in hyperlipidemic patients  

Microsoft Academic Search

Atorvastatin is an established HMG-CoA reductase inhibitor which effectively reduces the plasma low density lipoprotein (LDL)-cholesterol level in hyperlipidemic patients. The present study was designed to investigate whether atorvastatin treatment can modify the biochemical content of oxidized LDL in hyperlipidemic patients and the ability of oxidized LDL to impair the endothelium-dependent relaxation of blood vessels. With atorvastatin (10 mg\\/day) treatment

Quansheng Zhu; Jason McMaster; David Mymin; Tom Dembinski; Grant Hatch; Patrick C. Choy; Edwin A. Kroeger



Amphiphilic polyvinyl alcohol adsorbent for the removal of low-density lipoprotein.  


Spacer can effectively reduce the steric hindrance and synergistic effect of the hydrophilic and hydrophobic ligands immobilized in adsorbents can improve the specific adsorption for low-density lipoprotein (LDL). In this paper, in order to improve the adsorption capacity for the Low-density lipoprotein-cholesterol (LDL-C), specifically, amphiphilic adsorbent based on polyvinyl alcohol (PVA) containing cholesterol ligand and sulfonic dextran ligands was synthesized. All kinds of factors affecting the synthesis yield and adsorption properties were studied in detail. Results showed that the amphiphilic PVA adsorbent has higher adsorption capacity for total cholesterol (TC), (LDL-C), triglyceride (TG), and lower adsorption capacity, and percentage for high-density lipoprotein-cholesterol (HDL-C), while the ligand ratio of cholesterol to sulfonic ligands is 1.57:1, the adsorption percentage and adsorption capacity for TC, LDL-C, TG, and HDL-C were 54.4%, 67.6%, 42.5%, 10.4% and 4.02, 3.612, 2.154, 0.168 mg/g, respectively. PMID:24813224

Yu, Yao Ting; Zhu, Huijun; Wang, Shenqi



Predicting the structure of apolipoprotein A-I in reconstituted high-density lipoprotein disks.  

PubMed Central

In reconstituted high-density lipoproteins, apolipoprotein A-I and phosphatidylcholines combine to form disks in which the amphipathic alpha-helices of apolipoprotein A-1 bind to the edge of a lipid bilayer core, shielding the hydrophic lipid tails from the aqueous environment. We have employed experimental data, sequence analysis, and molecular modeling to construct an atomic model of such a reconstituted high-density lipoprotein disk consisting of two apolipoprotein A-I proteins and 160 palmitoyloleoylphosphatidylcholine lipids. The initial globular domain (1-47) of apolipoprotein A-I was excluded from the model, which was hydrated with an 8-A shell of water molecules. Molecular dynamics and simulated annealing were used to test the stability of the model. Both head-to-tail and head-to-head forms of a reconstituted high-density lipoprotein were simulated. In our simulations the protein contained and adhered to the lipid bilayer while providing good coverage of the lipid tails. Images FIGURE 1 FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 7 FIGURE 8 PMID:9370429

Phillips, J C; Wriggers, W; Li, Z; Jonas, A; Schulten, K




Technology Transfer Automated Retrieval System (TEKTRAN)

To test the hypothesis whether determination of high-density lipoprotein (HDL) subpopulations provides more power to predict recurrent cardiovascular disease (CVD) events (nonfatal myocardial infarction, coronary heart disease death, and stroke) than traditional risk factors in the Veterans Affairs ...


Low-density lipoprotein, its susceptibility to oxidation and the role of lipoprotein-associated phospholipase A2 and carboxyl ester lipase lipases in atherosclerotic plaque formation  

PubMed Central

An increased level of low-density lipoprotein (LDL) is a very well established risk factor of coronary artery disease (CAD). Unoxidized LDL is an inert transport vehicle of cholesterol and other lipids in the body and is thought to be atherogenic. Recently it has been appreciated that oxidized products of LDL are responsible for plaque formation properties previously attributed to the intact particle. The goal of this article is to review the recent understanding of the LDL oxidation pathway. The role of oxidized products and key enzymes (lipoprotein-associated phospholipase A2 and carboxyl ester lipase) are also extensively discussed in the context of clinical conditions. PMID:23515030

?urawski, Jakub; Zuchowski, Bartosz; Kubacki, Tomasz; Murawa, Dawid; Wiktorowicz, Krzysztof; Wysocki, Henryk



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



Metabolism of lipoproteins in nonhuman primates. Reduced secretion of very low density lipoproteins in squirrel monkeys with diet-induced hypercholesterolemia.  


We have studied the effects of diet-induced hypercholesterolemia on the rates of secretion of triglycerides into the plasma of fasted squirrel monkeys. Two groups of monkeys were studied: control animals which were fed a semipurified diet not associated with hyperlipemia (plasma cholesterol 127 +/- 8 mg/100 ml), and animals made hypercholesterolemic (plasma cholesterol 307 +/- 31 mg/100 ml) by being fed a diet containing 25% butter and 0.5% cholesterol. After intravenous infusion of Triton WR 1339 (300 mg/kg body wt), plasma triglycerides increased almost linearly for 9-12 hours. Analysis of individual lipoproteins separated by ultracentrifugation showed that newly secreted triglycerides were present almost exclusively in the very low density lipoprotein fraction. The rates of triglyceride secretion in the hypercholesterolemic group of monkeys (5.15 +/- 0.86 mg/kg/hr) were less than half those of the control animals (10.96 +/- 2.15 mg/kg/hr). We suggest that in monkeys with diet-induced hypercholesterolemia high concentrations of plasma low density lipoproteins may inhibit the synthesis and/or secretion of their parent very low density lipoprotein molecules into the circulation. PMID:173353

Illingworth, D R; Whipple, L E; Portman, O W



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



High-density lipoprotein as a modulator of platelet and coagulation responses.  


Platelets and coagulation factors are involved in the process of haemostasis, which ensures undisturbed blood flow upon vessel wall damage. However, excessive platelet aggregation and/or coagulation may lead to arterial or venous thrombosis. Pro-atherogenic lipoproteins, including native and oxidized low-density lipoprotein (LDL), are associated with an increased susceptibility to thrombosis. In contrast, numerous epidemiological studies have established an inverse correlation between high-density lipoprotein (HDL) levels and the risk for thrombosis. In addition to its role in reverse cholesterol transport, HDL also interacts with platelets, the coagulation cascade, and the vascular endothelium. Native HDL prevents platelet hyperreactivity by limiting intraplatelet cholesterol overload, as well as by modulating platelet signalling pathways after binding platelet HDL receptors such as scavenger receptor class B type I (SR-BI) and apoER2'. The antithrombotic properties of native HDL are also related to the suppression of the coagulation cascade and stimulation of clot fibrinolysis. Furthermore, HDL stimulates the endothelial production of nitric oxide and prostacyclin, which are potent inhibitors of platelet activation. Thus, HDL's antithrombotic actions are multiple and therefore, raising HDL may be an important therapeutic strategy to reduce the risk of arterial and venous thrombosis. PMID:24891399

van der Stoep, Marco; Korporaal, Suzanne J A; Van Eck, Miranda



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


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

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



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))



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



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


We previously reported that upper thoracic exposure to ionizing radiation (IR) accelerates fatty streak formation 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 levels. We thus proposed that IR promotes changes in the artery wall that enhance the deposition of lipoprotein lipids. To address this hypothesis, we examined the effects of IR on aortic accumulation and degradation of low density lipoproteins (LDL). Ten-week-old C57BL/6 mice were exposed to a single (8-Gy) dose of (60)Co radiation to the upper thoracic area or were sham irradiated (controls) and were then placed on the high fat diet. Five days postexposure, the mice received either (125)I-labeled LDL ((125)I-LDL) (which was used to measure intact LDL) or (125)I-labeled tyramine cellobiose ((125)I-TC)-LDL (which was used to measure both intact and cell-degraded LDL) via tail vein injection. On the basis of trichloroacetic acid (TCA)-precipitable counts in retroorbital blood samples, > or =95% of donor LDL was cleared within 24 h and there were no differences in time-averaged plasma concentrations of the two forms of LDL among irradiated and control mice. Aortic values increased markedly within the first hour and thereafter exhibited a slow increase up to 24 h. There were no differences between irradiated and control mice at 1 h, when values primarily reflected LDL entry, but a divergence was observed thereafter. At 24 h, (125)I-TC-associated counts were 1.8-fold higher in irradiated mice (P = 0.10). In contrast, (125)I-LDL-associated counts were 30% lower in irradiated mice (P< 0.05), suggesting that most of the retained (125)I-TC was associated with LDL degradation products. Consistent with the proposed involvement of oxidative or redox-regulated events, IR-induced LDL degradation was lower in SOD-transgenic than wild-type mice (P<0.05). The importance of LDL oxidation was suggested by observations that IR-induced LDL degradation was significantly reduced by preenriching LDL with alpha-tocopherol. On the basis of these results, we propose that IR elicits SOD-inhibitable changes in the artery wall that enhance LDL oxidation and degradation leading to the deposition of LDL-borne lipids. These studies provide additional support for the role of oxidation in lipoprotein lipid deposition and atherogenesis and suggest that IR promotes an arterial environment that stimulates this process in vivo. PMID:11013309

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



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

Technology Transfer Automated Retrieval System (TEKTRAN)

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


Cellular uptake and photosensitizing properties of anticancer porphyrins in cell membranes and low and high density lipoproteins.  


The mechanisms of the phototoxic effect of anticancer porphyrins used in the photodynamic therapy (PDT) of tumours are not yet completely understood. Irradiation of porphyrins gives rise to singlet oxygen which reacts with key residues of proteins, polyunsaturated fatty acids and cholesterol in membranes, leading to inactivation of various enzymes and transporters. Lipoproteins, mainly low density lipoproteins (LDL), are efficient carriers of anticancer porphyrins in blood and can deliver these photosensitizers to tissues through the apolipoprotein (apo) B/E specific LDL receptor pathway. In this review, we discuss some aspects of anticancer porphyrin transport, cellular uptake and photosensitizing properties in cell membranes and lipoproteins. PMID:2121939

Maziere, J C; Santus, R; Morliere, P; Reyftmann, J P; Candide, C; Mora, L; Salmon, S; Maziere, C; Gatt, S; Dubertret, L



Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E.  

PubMed Central

Apo E is a key molecule in the lipoprotein metabolism; thus, genetic manipulation of apo E may prove useful in the treatment of hypercholesterolemia. To test the feasibility of this idea, we have generated low density lipoprotein receptor (LDLR) knockout mice that overexpress the rat apo E transgene (ETg+/+:LDLRKO), and compared their plasma lipoprotein profiles with those of nonexpressing LDLR knockout mice (ETg-/-:LDLRKO). On a normal chow diet, the mean plasma cholesterol level of ETg+/+:LDLRKO mice was significantly lower than that of ETg-/-:LDLRKO mice (189 versus 240 mg/dl, P < 0. 01). The LDL fraction was selectively reduced in the ETg+/+:LDLRKO mice. Despite the challenge with an atherogenic diet, cholesterol lowering was persistently observed and fatty streak lesions in the aortic sinus were significantly suppressed in the mice overexpressing apo E. These results imply that stimulation of hepatic production of apo E may be used as a promising adjunctive therapy for homozygous familial hypercholesterolemia. PMID:9664080

Osuga, J; Yonemoto, M; Yamada, N; Shimano, H; Yagyu, H; Ohashi, K; Harada, K; Kamei, T; Yazaki, Y; Ishibashi, S



Specificity of Receptor-Mediated Recognition of Malondialdehyde-Modified Low Density Lipoproteins  

NASA Astrophysics Data System (ADS)

Blood-borne human monocytes and macrophages derived from human monocytes in vitro express an active low density lipoprotein (LDL) receptor and an active receptor for negatively charged proteins, the scavenger receptor. When < 15% of the lysine residues of human LDL were modified by malondialdehyde while the lipoprotein was in solution, recognition and uptake of the modified lipoprotein occurred via the LDL receptor. Further modification resulted in threshold recognition and uptake by the scavenger receptor with concomitant loss of recognition by the LDL receptor. The rate of degradation via the LDL receptor pathway was inversely related to the degree of modification whereas that mediated by the scavenger receptor was independent of the extent of incorporation of malondialdehyde once threshold recognition was achieved. In contrast to the interaction of LDL with malondialdehyde in solution, modification of < 15% of the lysine residues of LDL adsorbed to heparin-Sepharose resulted in recognition and uptake by the scavenger receptor. The scavenger receptor-mediated uptake of malondialdehyde-modified LDL may be dependent on formation of recognition sites involving specific modified lysine residues or changes in the conformation of LDL induced by neutralization of specific lysine residues of the apoB polypeptides or both.

Haberland, Margaret E.; Fogelman, Alan M.; Edwards, Peter A.



Low-density lipoprotein cholesterol suppresses apoptosis in human multiple myeloma cells.  


Multiple myeloma (MM) is an incurable disease accompanied by low plasma levels of low-density lipoprotein cholesterol (LDL-c). The significance of altered cholesterol metabolism in the pathophysiology of MM remains elusive. Although it has been hypothesized that myeloma cells depend on exogenous cholesterol for its survival, the role of LDL-c on myeloma cells has not been elucidated. To evaluate the impact of exogenous LDL-c on cell viability, three human myeloma cell lines (RPMI-8226, NCI-H929, and U-266B1) were grown in the presence or absence of lipoproteins. Cell viability was markedly reduced in the absence of lipoproteins in sera. However, exogenous LDL-c improved cell viability. We showed that reduced cell viability was associated with increased levels of cleaved caspase-3, whereas proliferation rate remained unchanged. Interestingly, exogenous LDL-c counteracted apoptosis in human myeloma cell lines and primary cultures of human myeloma cells. Thus, our results demonstrated that LDL-c is an important anti-apoptotic factor for myeloma cells and begin to explain the hypocholesterolemia observed in patients with MM. PMID:21538060

Tirado-Vélez, Jose Manuel; Benítez-Rondán, Alicia; Cózar-Castellano, Irene; Medina, Francisco; Perdomo, Germán



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

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



Low-density lipoprotein cholesterol versus particle number in middle school children  

PubMed Central

Objectives To characterize lipids and lipoproteins in a diverse school-based cohort and identify features associated with discordance between low-density lipoprotein cholesterol (LDL-C) and LDL particle (LDL-P). Study design Sixth grade children enrolled in the HEALTHY trial (n=2,384; mean age 11.3 ± 0.6 yr; 54.2% female) were evaluated for standard lipids, lipoprotein particles measured by nuclear magnetic resonance, and homeostatic model of insulin resistance (HOMA-IR). Characteristics of subgroups with values of LDL-C and LDL-P discordant by >20 percentile units, an amount reasoned to be clinically significant, were compared. Results Four hundred twenty-eight (18%) of children were in the LDL-P < LDL-C subgroup and 375 (16%) in the LDL-P > LDL-C subgroup. Those with LDL-P > LDL-C had significantly higher BMI, waist circumference, HOMA-IR, triglycerides, systolic and diastolic blood pressure, and reflected a greater Hispanic ethnic composition but fewer of black race than both the concordant (LDL-P ? LDL-C) and opposite discordant (LDL-P < LDL-C) subgroups. Conclusions There is as much lipoprotein cholesterol compositional heterogeneity in 6th graders as has been described in adults and a discordant atherogenic phenotype of LDL-P > LDL-C, common in obesity, is often missed when only LDL-C is considered. Conversely, many children with moderate-risk cholesterol measures (75th to 99th percentile) have a lower LDL particle burden. PMID:23415622

Mietus-Snyder, Michele; Drews, Kimberly L.; Otvos, James D.; Willi, Steven M.; Foster, Gary D.; Jago, Russell; Buse, John B.



Native and acetylated low density lipoprotein metabolism in proliferating and quiescent bovine endothelial cells in culture.  


Lipoprotein binding and metabolism in actively dividing (sparse) and quiescent (confluent) bovine aortic endothelial cells (EC) were compared quantitatively using 125I-labelled lipoproteins. The amounts of receptor-bound low density lipoproteins (LDL) decreased five- to ten-fold as the cultures progressed from sparse to confluent morphology. High affinity receptor-bound LDL levels were extremely low in confluent EC and accounted for the inability of confluent EC to internalize and degrade significant amounts of LDL. Conversely, the amounts of acetylated LDL (acLDL) bound and degraded via distinct sites increased at least five-fold during EC growth to confluence. LDL binding and metabolism in individual cells was assessed by fluorescence microscopy using 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labelled lipoproteins or fluorescein-conjugated antibodies. LDL and acLDL bound to the surfaces of sparse EC, at either 4 degrees or 37 degrees C, in a random distribution of fine punctate foci, contrary to a previous report. EC therefore appear to resemble fibroblasts in their distribution of surface LDL receptors. No binding or uptake of LDL was seen in confluent EC. Patterns of acLDL binding and uptake in confluent EC resembled those of LDL in sparse EC. Intracellular LDL and acLDL occurred as perinuclear accumulations of large fluorescent foci in sparse EC. Regeneration experiments were carried out in artificially wounded confluent cultures and renewed LDL receptor activity was shown in actively-dividing cells which had migrated into the "wounded" areas. We conclude that quiescent endothelial cells metabolize little LDL via the LDL-receptor pathway due to a drastically reduced number of receptors in confluent cells. This contrasts with the ability of confluent cells to metabolize relatively large amounts of acLDL via a receptor-mediated mechanism. PMID:3979404

Sanan, D A; Strümpfer, A E; van der Westhuyzen, D R; Coetzee, G A



Overexpression of hepatic lipase in transgenic mice decreases apolipoprotein B-containing and high density lipoproteins. Evidence that hepatic lipase acts as a ligand for lipoprotein uptake.  


To determine the mechanisms by which human hepatic lipase (HL) contributes to the metabolism of apolipoprotein (apo) B-containing lipoproteins and high density lipoproteins (HDL) in vivo, we developed and characterized HL transgenic mice. HL was localized by immunohistochemistry to the liver and to the adrenal cortex. In hemizygous (hHLTg+/0) and homozygous (hHLTg+/+) mice, postheparin plasma HL activity increased by 25- and 50-fold and plasma cholesterol levels decreased by 80% and 85%, respectively. In mice fed a high fat, high cholesterol diet to increase endogenous apoB-containing lipoproteins, plasma cholesterol decreased 33% (hHLTg+/0) and 75% (hHLTg+/+). Both apoB-containing remnant lipoproteins and HDL were reduced. To extend this observation, the HL transgene was expressed in human apoB transgenic (huBTg) and apoE-deficient (apoE-/-) mice, both of which have high plasma levels of apoB-containing lipoproteins. (Note that the huBTg mice that were used in these studies were all hemizygous for the human apoB gene.) In both the huBTg,hHLTg+/0 mice and the apoE-/-,hHLTg+/0 mice, plasma cholesterol decreased by 50%. This decrease was reflected in both the apoB-containing and the HDL fractions. To determine if HL catalytic activity is required for these decreases, we expressed catalytically inactive HL (HL-CAT) in apoE-/- mice. The postheparin plasma HL activities were similar in the apoE-/- and the apoE-/-,HL-CAT+/0 mice, reflecting the activity of the endogenous mouse HL and confirming that the HL-CAT was catalytically inactive. However, the postheparin plasma HL activity was 20-fold higher in the apoE-/-,hHLTg+/0 mice, indicating expression of the active human HL. Immunoblotting demonstrated high levels of human HL in postheparin plasma of both apoE-/-,hHLTg+/0 and apoE-/-,HL-CAT+/0 mice. Plasma cholesterol and apoB-containing lipoprotein levels were approximately 60% lower in apoE-/-,HL-CAT+/0 mice than in apoE-/- mice. However, the HDL were only minimally reduced. Thus, the catalytic activity of HL is critical for its effects on HDL but not for its effects on apoB-containing lipoproteins. These results provide evidence that HL can act as a ligand to remove apoB-containing lipoproteins from plasma. PMID:9442022

Dichek, H L; Brecht, W; Fan, J; Ji, Z S; McCormick, S P; Akeefe, H; Conzo, L; Sanan, D A; Weisgraber, K H; Young, S G; Taylor, J M; Mahley, R W



Plasma high density lipoprotein subgroup distribution in rats fed diets with varying amounts of sucrose and sunflower oil  

Microsoft Academic Search

The effect of varying the dietary sunflower oil\\/sucrose (SO\\/SU) ratio on rat plasma lipid concentration and lipoprotein distribution\\u000a was studied. Four groups of 10 rats were fed for 4 weeks diets with varying SO\\/SU ratios. Lipoprotein components were then\\u000a estimated in whole plasma and after cumulative density ultracentrifugation. Whole plasma triacylglycerol (TG), total cholesterol\\u000a (TC) and free cholesterol (FC) decreased

Arne T. Høstmark; Øystein Spydevold; Einar Lystad; Eva Kristensen; Ida Goffeng Bay



Plasma oxidized low density lipoprotein cholesterol correlates inversely with testosterone in young adult male smokers  

PubMed Central

Introduction There are indications that oxidized low density lipoprotein cholesterol (Ox-LDLC) may play an important role in cardiovascular disease (CVD) events. In most developing countries, the interplay between the different lipid fractions and cigarette smoking has not been studied. This study assessed the effect of cigarette smoking on the alterations in plasma lipid fractions and their associations with the gonadal hormone, testosterone (T). Methods One hundred and sixty male participants, consisting of eighty smokers and eighty apparently healthy non-smokers were recruited. Anthropometric indices and biochemical parameters were determined using standard procedures. Results Significant increases were obtained in plasma total cholesterol (TC), triglyceride (TG), oxidized low density lipoprotein (Ox-LDLC) and Ox-LDLC/TT ratio (p<0.001) in smokers compared with the non-smokers. Plasma high density cholesterol (HDLC) (p<0.001) was significantly reduced in smokers compared with the non-smokers. The plasma mean T result was not significantly different from the non-smokers, but inversely correlated with Ox-LDLC and significantly correlated with the lipids and lipoproteins. Significantly high plasma TC, TG and LDLC (p<0.001) and low HDLC (p<0.001) were also obtained in smokers when co-founding factors such as duration and number of cigarette smoked per day were applied. Conclusion This study showed an inverse correlation between Ox-LDLC and testosterone as well as strong association between the number of tobacco and cigarettes usage per day. These changes in part, could be major causes of premature CVD and decreased fertility in young adults.

Ebesunun, Maria Onomhaguan; Bankole, Olurakinyo Lanre; Oduwole, Olayiwola



Density distribution, characterization, and comparative aspects of the major serum lipoproteins in the common marmoset (Callithrix jacchus), a New World primate with potential use in lipoprotein research.  


Qualitative, quantitative, and comparative aspects of the serum lipoprotein profile in the Common marmoset (Callithrix jacchus), a New World primate, are described. Density gradient ultracentrifugation was used to evaluate lipoprotein distribution and to establish criteria for isolation of discrete molecular fractions. The major lipoprotein classes banded isopycnically on the gradient with the following hydrated densities: VLDL, d less than 1.017 g/mL; LDL, d = 1.027--1.055 g/mL; HDL fraction I, d = 1.070--1.127 g/mL; and HDL fraction II, d = 1.127--1.156 g/mL. Electrophoretic, immunological, and electron microscopic analyses attested to the purity of these fractions: the characteristics of each were assessed by chemical analysis, electron microscopy, immunological techniques, and polyacrylamide gel electrophoresis of their protein moieties. Marmoset VLDL and LDL were closely akin to those of man in size and chemical composition, although the former were richer in triglyceride; electrophoretic and immunological data showed the major protein component of VLDL and LDL to be a counterpart to human apo-B. The two HDL subfractions, i.e., HDL-I and HDL-II, corresponded in size and chemical composition to human HDL2 and HDL3, respectively, although slight differences in neutral lipid content were detected. By immunological and electrophoretic criteria, the major apolipoprotein of marmoset HDL was analogous to human apo-AI. In contrast, marked dissimilarities were evident in the complements of low molecular weight, tetramethylurea-soluble polypeptides of marmoset and human lipoproteins. Quantitatively, the human and marmoset lipoprotein profiles were not dissimilar, although HDL was the major class (approximately 50%); in fasting animals, serum concentrations of VLDL, LDL, and HDL were 50--90, 170--280, and 338--408 mg/dL, respectively. C. jacchus was distinct from man in displaying a greater proportion of its total HDL in the less dense (HDL-II) subfraction (marmoset HDL-I/HDL-II = approximately 4:1; human HDL2/HDL3 = approximately 1:3). These data indicate that, as an experimental animal for lipoprotein research, the Common marmoset combines the advantages of ready availability and maintenance with a serum lipoprotein profile which resembles, in many qualitative and quantitative aspects, that found in man. PMID:227447

Chapman, M J; Mc Taggart, F; Goldstein, S



Synthetic Nano-Low Density Lipoprotein as Targeted Drug DeliveryVehicle for Glioblastoma Multiforme  

SciTech Connect

This paper discribes a synthetic low density lipoprotein(LDL) made by complexing a 29 amino acid that consists of a lipid bindingdomain and the LDL receptor binding domain with a lipid microemulsion.The nano-LDL particles were intermdiate in size between LDL and HDL andbound to LDL receptors on GBM brain tumor cells. Synthetic nano-LDLuptake by GBM cells was LDL receptor specific and dependent on cellreceptor number. It is suggested that these synthetic particles can serveas a delivery vehicle for hydophobic anti-tumor drugs by targeting theLDL receptor.

Nikanjam, Mina; Blakely, Eleanor A.; Bjornstad, Kathleen A.; Shu,Xiao; Budinger, Thomas F.; Forte, Trudy M.



Oxidation of cholesterol does not alter significantly its uptake into high-density lipoprotein particles.  


Using replica exchange umbrella sampling we calculated free energy profiles for uptake of cholesterol and one of its oxysterols (7-ketocholesterol) from an aqueous solution into a high-density lipoprotein particle. These atomistic molecular dynamics simulations show that both sterols are readily taken up from the aqueous solution with comparable free energy minima at the surface of the particle of -17 kcal/mol for cholesterol and -14 kcal/mol for 7-ketocholesterol. Moreover, given its preferred position at the particle surface, 7-ketocholesterol is expected to be able to participate directly in biological signaling processes. PMID:25768721

Karilainen, Topi; Timr, Št?pán; Vattulainen, Ilpo; Jungwirth, Pavel



Are lower levels of low-density lipoprotein cholesterol beneficial? A review of recent data  

Microsoft Academic Search

In the 1960s, epidemiologic studies established a link between elevated serum cholesterol and increased risk of cardiovascular\\u000a events. Extensive clinical trial data subsequently highlighted 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors\\u000a (ie, statins) as the most effective pharmacotherapy for lowering low-density lipoprotein (LDL) cholesterol, and showed that\\u000a statin-mediated LDL cholesterol reductions were associated with significant improvements in cardiovascular outcomes. Such\\u000a findings are

Anders G. Olsson



The Mystery of High-density Lipoprotein: Quantity or Quality? Update on Therapeutic Strategies.  


This review summarizes the data challenging the concept that cardiovascular protection through high-density lipoprotein (HDL) is only associated with its serum concentration. This conventional impression about its protective role now appears obsolete. New aspects of its mechanisms are revealed and novel therapeutic strategies are based on them. However, data from long-term cost-effectiveness studies of treating HDL are still needed. There is a need for biomarkers that represent the functional characteristics of HDL in order to better quantify the total cardiovascular risk. PMID:25813792

Katsi, Vasiliki; Kallistratos, Manolis S; Pavlidis, Antonios N; Karpettas, Nikos; Skoumas, Ioannis; Pavleros, Nikonas; Manolis, Athanasios J; Pitsavos, Christos; Tousoulis, Dimitris; Stefanadis, Christodoulos; Kallikazaros, Ioannis



Combined Roles of Human IgG Subclass, Alternative Complement Pathway Activation, and Epitope Density in the Bactericidal Activity of Antibodies to Meningococcal Factor H Binding Protein  

PubMed Central

Meningococcal vaccines containing factor H binding protein (fHbp) are in clinical development. fHbp binds human fH, which enables the meningococcus to resist complement-mediated bacteriolysis. Previously, we found that chimeric human IgG1 mouse anti-fHbp monoclonal antibodies (MAbs) had human complement-mediated bactericidal activity only if the MAb inhibited fH binding. Since IgG subclasses differ in their ability to activate complement, we investigated the role of human IgG subclasses on antibody functional activity. We constructed chimeric MAbs in which three different murine fHbp-specific binding domains were each paired with human IgG1, IgG2, or IgG3. Against a wild-type group B isolate, all three IgG3 MAbs, irrespective of their ability to inhibit fH binding, had bactericidal activity that was >5-fold higher than the respective IgG1 MAbs, while the IgG2 MAbs had the least activity. Against a mutant with increased fHbp expression, the anti-fHbp MAbs elicited greater C4b deposition (classical pathway) and greater bactericidal activity than against the wild-type strain, and the IgG1 MAbs had similar or greater activity than the respective IgG3 MAbs. The bactericidal activity against both wild-type and mutant strains also was dependent, in part, on activation of the alternative complement pathway. Thus, at lower epitope density in the wild-type strain, the IgG3 anti-fHbp MAbs had the greatest bactericidal activity. At a higher epitope density in the mutant, the IgG1 MAbs had similar or greater bactericidal activity than the IgG3 MAbs, and the activity was less dependent on the inhibition of fH binding than at a lower epitope density. PMID:22064712

Giuntini, Serena; Reason, Donald C.



Preferential enrichment of large-sized very low density lipoprotein populations with transferred cholesteryl esters  

SciTech Connect

The effect of lipid transfer proteins on the exchange and transfer of cholesteryl esters from rat plasma HDL2 to human very low (VLDL) and low density (LDL) lipoprotein populations was studied. The use of a combination of radiochemical and chemical methods allowed separate assessment of (/sup 3/H)cholesteryl ester exchange and of cholesteryl ester transfer. VLDL-I was the preferred acceptor for transferred cholesteryl esters, followed by VLDL-II and VLDL-III. LDL did not acquire cholesteryl esters. The contribution of exchange of (/sup 3/H)cholesteryl esters to total transfer was highest for LDL and decreased in reverse order along the VLDL density range. Inactivation of lecithin: cholesterol acyltransferase (LCAT) and heating the HDL2 for 60 min at 56 degrees C accelerated transfer and exchange of (/sup 3/H)cholesteryl esters. Addition of lipid transfer proteins increased cholesterol esterification in all systems. The data demonstrate that large-sized, triglyceride-rich VLDL particles are preferred acceptors for transferred cholesteryl esters. It is suggested that enrichment of very low density lipoproteins with cholesteryl esters reflects the triglyceride content of the particles.

Eisenberg, S.



Characterization of ? 2-macroglobulin receptor low density lipoprotein receptor-related protein ( ? 2MR\\/LRP) in White Carneau pigeon peritoneal macrophages: its role in lipoprotein metabolism  

Microsoft Academic Search

White Carneau pigeons develop atherosclerosis naturally, and at an accelerated rate with cholesterol feeding. Macrophages play a central role in the pathogenesis of atherosclerosis in pigeons, as they do in man. The purpose of this study was to determine whether pigeon macrophages express the ?2-macroglobulin receptor\\/low density lipoprotein receptor-related protein (?2 MR\\/LRP) and whether this receptor would recognize ?-VLDL, the

Toru Seo; Heuy-Cheng Wang; Steven R Feldman; Richard W St. Clair



Postprandial lipoprotein metabolism; VLDL vs chylomicrons  

PubMed Central

Since Zilversmit first proposed postprandial lipemia as the most common risk of cardiovascular disease, chylomicrons (CM) and CM remnants have been thought to be the major lipoproteins which are increased in the postprandial hyperlipidemia. However, it has been shown over the last two decades that the major increase in the postprandial lipoproteins after food intake occurs in the very low density lipoprotein (VLDL) remnants (apoB100 particles), not CM or CM remnants (apoB48 particles). This finding was obtained using the following three analytical methods; isolation of remnant-like lipoprotein particles (RLP) with specific antibodies, separation and detection of lipoprotein subclasses by gel permeation HPLC and determination of apoB48 in fractionated lipoproteins by a specific ELISA. The amount of the apoB48 particles in the postprandial RLP is significantly less than the apoB100 particles, and the particle sizes of apoB48 and apoB100 in RLP are very similar when analyzed by HPLC. Moreover, CM or CM remnants having a large amount of TG were not found in the postprandial RLP. Therefore, the major portion of the TG which is increased in the postprandial state is composed of VLDL remnants, which have been recognized as a significant risk for cardiovascular disease. PMID:21531214

Nakajima, Katsuyuki; Nakano, Takamitsu; Tokita, Yoshiharu; Nagamine, Takeaki; Inazu, Akihiro; Kobayashi, Junji; Mabuchi, Hiroshi; Stanhope, Kimber L.; Havel, Peter J.; Okazaki, Mitsuyo; Ai, Masumi; Tanaka, Akira



Uptake of chemically modified low density lipoproteins in vivo is mediated by specific endothelial cells  

PubMed Central

Acetoacetylated (AcAc) and acetylated (Ac) low density lipoproteins (LDL) are rapidly cleared from the plasma (t1/2 approximately equal to 1 min). Because macrophages, Kupffer cells, and to a lesser extent, endothelial cells metabolize these modified lipoproteins in vitro, it was of interest to determine whether endothelial cells or macrophages could be responsible for the in vivo uptake of these lipoproteins. As previously reported, the liver is the predominant site of the uptake of AcAc LDL; however, we have found that the spleen, bone marrow, adrenal, and ovary also participate in this rapid clearance. A histological examination of tissue sections, undertaken after the administration of AcAc LDL or Ac LDL (labeled with either 125I or a fluorescent probe) to rats, dogs, or guinea pigs, was used to identify the specific cells binding and internalizing these lipoproteins in vivo. With both techniques, the sinusoidal endothelial cells of the liver, spleen, bone marrow, and adrenal were labeled. Less labeling was noted in the ovarian endothelia. Uptake of AcAc LDL by endothelial cells of the liver, spleen, and bone marrow was confirmed by transmission electron microscopy. These data suggest uptake through coated pits. Uptake of AcAc LDL was not observed in the endothelia of arteries (including the coronaries and aorta), veins, or capillaries of the heart, testes, kidney, brain, adipose tissue, and duodenum. Kupffer cells accounted for a maximum of 14% of the 125I-labeled AcAc LDL taken up by the liver. Isolated sinusoidal endothelial cells from the rat liver displayed saturable, high affinity binding of AcAc LDL (Kd = 2.5 X 10(- 9) M at 4 degrees C), and were shown to degrade AcAc LDL 10 times more effectively than aortic endothelial cells. These data indicate that specific sinusoidal endothelial cells, not the macrophages of the reticuloendothelial system, are primarily responsible for the removal of these modified lipoproteins from the circulation in vivo. PMID:3965468



Density profile and cholesterol concentration of serum lipoproteins in experimental animals and human subjects on hypercholesterolaemic diets.  


The density profile of Sudan black stained serum lipoproteins was studied in human subjects and various animal species on diets supplemented with cholesterol. In the animals studied (rabbits, calves, mice, chickens, rats and guinea-pigs), the feeding of cholesterol resulted in an elevation of serum cholesterol levels together with marked changes in the density profile and the cholesterol concentration of the serum lipoproteins. Large differences between animal species in their response to dietary cholesterol were found. In a human subject, an increased concentration of serum cholesterol due to the consumption of a diet supplemented with six egg yolks per day was reflected in an elevated level of LDL cholesterol, while changes in the density profile of stained serum lipoproteins were not observed. In subjects with familial type III and type IV hyperlipoproteinaemia, marked differences in the density profile of lipoproteins were found when compared with that of normolipoproteinaemic subjects. The density profile of stained lipoproteins in the type III patients was remarkably similar to that in cholesterol-fed chickens and lean Zucker rats. PMID:6713826

Terpstra, A H; Beynen, A C



Italian multicenter study on low-density lipoprotein apheresis Working Group 2009 survey.  


We present results of the second survey of the Italian Multicenter Study on Low-Density Lipoprotein Apheresis (IMSLDLa-WG/2). The study involved 18 centers in 2009, treating 66 males and 35 females, mean age 47 ± 18 years. Mean age for initiation of drug treatment before low-density lipoprotein apheresis (LDLa) was 31 ± 18 years, mean age to the first LDLa was 37 ± 20 years and average duration of treatment was 9 ± 6 years. The techniques used included direct adsorption of lipids, dextran sulfate cellulose adsorption, heparin-mediated low-density lipoprotein (LDL) precipitation, cascade filtration, and plasma exchange. The mean treated plasma/blood volumes/session were 3127 ± 518 mL and 8666 ± 1384 mL, respectively. The average plasma volume substituted was 3500 ± 300 mL. Lipid therapy before LDLa included ezetimibe, statins, ?-3 fatty acids and fenofibrate. Baseline mean LDL cholesterol (LDLC) levels were 386 ± 223 mg/dL. The mean before/after apheresis LDLC level decreased by 67% from 250 ± 108 mg/dL (P = 0.05 vs. baseline) to 83 ± 37 mg/dL (P = 0.001 vs. before). Baseline mean Lipoprotein(a) [Lp(a)] level was 179 ± 136 mg/dL. Mean before/after apheresis Lp(a) level decreased by 71% from 133 ± 120 mg/dL (P = 0.05 vs. baseline) to 39 ± 44 mg/dL (P = 0.001 vs. before). Major and minor side effects occurred in 27 and 62 patients, respectively. Among patients with coronary artery disease (CAD), 62.3% had coronary angiography and 50.4% coronary revascularization before LDLa. Single vessel, double vessel and triple vessel CAD occurred in 19 (30.1%), 15 (23.8%) and 29 (46%) patients, respectively. Both CAD and extra-CAD occurred in 41.5%, 39% had hypertension, 9.9% were smokers, 9.9% consumed alcohol and 42% were physically active. Ischemic cardiovascular events were not observed in any patient over 9 ± 6 years of treatment. Two centers have also treated 34 patients (females: 17/males 17; no. sessions: 36; average plasma volume treated: 3000 mL) for sudden hearing loss (SHL). Relief of symptoms was obtained, independently of the system used (HELP; cascade-filtration). PMID:23551673

Stefanutti, Claudia; Morozzi, Claudia; Di Giacomo, Serafina



Plasma low density lipoprotein transport kinetics in noninsulin-dependent diabetes mellitus.  

PubMed Central

Plasma low density lipoprotein (LDL) transport kinetics were determined from the disappearance of 125I-LDL injected into age- and weight-matched groups of 13 normal subjects, 20 mild diabetics, and 8 moderately severe diabetic patients (fasting plasma glucose less than 150 and greater than 150 mg/100 ml, respectively). In mild diabetics, LDL apo-lipoprotein-B (apo-B) synthetic rate (SR) was significantly greater than normal. The fractional catabolic rate (FCR), however, was also increased so that plasma LDL concentration remained normal. In moderately severe diabetics, LDL SR was normal but FCR was reduced resulting in increased plasma LDL cholesterol and apo-B concentrations. In normal subjects, moderate obesity was associated with increased LDL secretion. In diabetic subjects, however, changes in LDL turnover were of equal magnitude in obese and nonobese patients. In normolipemic and hyperlipemic mild diabetic subjects with equal degrees of glucose intolerance, both LDL apo-B SR and FCR were greater than normal. The magnitude of these increases, however, was lower in the hyperlipemic individuals. Stepwise regression analysis revealed that both LDL SR and FCR correlated positively and linearly with insulin response to glucose loading, but negatively and curvilinearly with fasting plasma glucose and glucose response. We propose that in noninsulin-dependent diabetes, mild hyperglycemia is accompanied by increased LDL turnover, despite normal plasma LDL levels, whereas moderately severe hyperglycemia is associated with decreased LDL catabolism, resulting in increased plasma LDL levels. These changes cannot be attributed to the presence of obesity or hypertriglyceridemia, and may relate to varying degrees of insulin resistance and decreased insulin secretion affecting plasma very low density lipoprotein (VLDL) secretion, VLDL conversion to LDL, and LDL catabolism. Both increased LDL turnover in mild diabetes and delayed removal of LDL in moderately severe diabetes could increase cholesterol ester availability to peripheral tissues, and may result in an increased risk of atherosclerosis. PMID:6338042

Kissebah, A H; Alfarsi, S; Evans, D J; Adams, P W



Relation of Black Race Between High Density Lipoprotein Cholesterol Content, High Density Lipoprotein Particles and Coronary Events (from the Dallas Heart Study).  


Therapies targeting high-density lipoprotein cholesterol content (HDL-C) have not improved coronary heart disease (CHD) outcomes. High-density lipoprotein particle concentration (HDL-P) may better predict CHD. However, the impact of race/ethnicity on the relations between HDL-P and subclinical atherosclerosis and incident CHD events has not been described. Participants from the Dallas Heart Study (DHS), a multiethnic, probability-based, population cohort of Dallas County adults, underwent the following baseline measurements: HDL-C, HDL-P by nuclear magnetic resonance imaging, and coronary artery calcium by electron-beam computed tomography. Participants were followed for a median of 9.3 years for incident CHD events (composite of first myocardial infarction, stroke, coronary revascularization, or cardiovascular death). The study comprised 1,977 participants free of CHD (51% women, 46% black). In adjusted models, HDL-C was not associated with prevalent coronary artery calcium (p = 0.13) or incident CHD overall (hazard ratio [HR] per 1 SD 0.89, 95% confidence interval [CI] 0.76 to 1.05). However, HDL-C was inversely associated with incident CHD among nonblack (adjusted HR per 1 SD 0.67, 95% CI 0.46 to 0.97) but not black participants (HR 0.94, 95% CI 0.78 to 1.13, pinteraction = 0.05). Conversely, HDL-P, adjusted for risk factors and HDL-C, was inversely associated with prevalent coronary artery calcium (p = 0.009) and with incident CHD overall (adjusted HR per 1 SD 0.73, 95% CI 0.62 to 0.86), with no interaction by black race/ethnicity (pinteraction = 0.57). In conclusion, in contrast to HDL-C, the inverse relation between HDL-P and incident CHD events is consistent across ethnicities. These findings suggest that HDL-P is superior to HDL-C in predicting prevalent atherosclerosis as well as incident CHD events across a diverse population and should be considered as a therapeutic target. PMID:25661572

Chandra, Alvin; Neeland, Ian J; Das, Sandeep R; Khera, Amit; Turer, Aslan T; Ayers, Colby R; McGuire, Darren K; Rohatgi, Anand



Effects of maximal doses of atorvastatin versus rosuvastatin on small dense low-density lipoprotein cholesterol levels  

Technology Transfer Automated Retrieval System (TEKTRAN)

Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipo...


Ammonium chloride causes reversible inhibition of low density lipoprotein receptor recycling and accelerates receptor degradation.  


The effects of the acidotropic agent, NH4Cl, on the recycling and turnover of low density lipoprotein (LDL) receptors were analyzed in human skin fibroblasts using ligand binding assays, [35S]methionine pulse-chase experiments, and electron microscopy. NH4Cl did not prevent receptor internalization but caused a marked redistribution of LDL receptors to intracellular sites (endosomes) that was completely dependent on the presence of apolipoprotein-B- or -E-containing ligands. Maximal inhibition of recycling was observed at LDL concentrations that only partially saturated receptors, suggesting that the receptors function as oligomers. In contrast, full receptor occupancy by the multivalent, apolipoprotein-E-containing beta-very low density lipoprotein was required for the same effect. The intracellular accumulation was reversible and the majority of receptors returned to the cell surface when NH4Cl was removed after short treatments. The rate of degradation of LDL receptors was greatly accelerated in the presence of NH4Cl and ligand, with a t1/2 of about 2 h (approximately 6 times faster than receptor degradation in the absence of NH4Cl). Neither the redistribution nor the accelerated loss of immunoprecipitable LDL receptors was observed in an LDL receptor internalization-defective mutant cell line. We conclude that NH4Cl inhibited the recycling specifically of occupied receptors, thereby accelerating their degradation, probably in endosomes. PMID:2303493

Grant, K I; Casciola, L A; Coetzee, G A; Sanan, D A; Gevers, W; van der Westhuyzen, D R



IgG-autoantibodies against oxidized low-density lipoprotein in ischemic stroke onset.  


In the arterial wall oxidized Low Density Lipoprotein is a pro-inflammatory chemotactic factor for macrophages and immunoreactive cells. The association between oxidized low density lipoprotein (oxLDL) and stroke is suspected, but not established. The plasma oxLDL level in patients with ischemic stroke would be increased and could serve as a marker of ischemic stroke. Serum oxLDL concentrations were determined in 267 ischemic stroke patients (mean age of 72.6.6 +/- 8.6 years) and in 125 age matched controls. Anti-oxLDL antibodies were measured by ELISA. It was investigated the relationship between the serum titers of anti-oxLDL and ischemic stroke onset (within 24 hours) as compared to healthy control subjects. Thirty-one percent (82/267) of the patients tested had higher anti-oxLDL levels than controls. Mean anti-oxLDL titer was 544.6 +/- 48.2 mU/mL vs 416.2 +/- 31.4 mU/mL respectively, statistically significantly higher than those of controls (p < 0.001). The high concentrations of IgG anti-oxLDL contribute to a cascade of events characterized as immunoinflammatory reactions of ischemic stroke. It is probable that humoral immunity plays a significant role in the very initial stages of ischemic stroke. We can deduce that immune response to oxLDL is of variable importance, regarding pathophysiologic process in the ischemic stroke. PMID:17236297

Cojocaru, Inimioara Mihaela; Cojocaru, M; Burcin, Cecilia



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



Lowering low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus  

PubMed Central

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia, insulin resistance, and/or progressive loss of ?-cell function. T2DM patients are at increased risk of micro- and macrovascular disease, and are often considered as representing an atherosclerotic coronary heart disease (CHD) risk equivalent. Interventions directed at glucose and lipid level control in T2DM patients may reduce micro- and macrovascular disease. The optimal T2DM agent is one that lowers glucose levels with limited risk for hypoglycemia, and with no clinical trial evidence of worsening CHD risk. Lipid-altering drugs should preferably reduce low-density lipoprotein cholesterol and apolipoprotein B (apo B) and have evidence that the mechanism of action reduces CHD risk. Statins reduce low-density lipoprotein cholesterol and apo B and have evidence of improving CHD outcomes, and are thus first-line therapy for the treatment of hypercholesterolemia. In patients who do not achieve optimal lipid levels with statin therapy, or who are intolerant to statin therapy, add-on therapy or alternative therapies may be indicated. Additional available agents to treat hypercholesterolemic patients with T2DM include bile acid sequestrants, fibrates, niacin, and ezetimibe. This review discusses the use of these alternative agents to treat hypercholesterolemia in patients with T2DM, either as monotherapy or in combination with statin therapy. PMID:25045281

Bays, Harold E



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



A Potential Neuroprotective Role of Apolipoprotein E-containing Lipoproteins through Low Density Lipoprotein Receptor-related Protein 1 in Normal Tension Glaucoma*  

PubMed Central

Glaucoma is an optic neuropathy and the second major cause of blindness worldwide next to cataracts. The protection from retinal ganglion cell (RGC) loss, one of the main characteristics of glaucoma, would be a straightforward treatment for this disorder. However, the clinical application of neuroprotection has not, so far, been successful. Here, we report that apolipoprotein E-containing lipoproteins (E-LPs) protect primary cultured RGCs from Ca2+-dependent, and mitochondrion-mediated, apoptosis induced by glutamate. Binding of E-LPs to the low density lipoprotein receptor-related protein 1 recruited the N-methyl-d-aspartate receptor, blocked intracellular Ca2+ elevation, and inactivated glycogen synthase kinase 3?, thereby inhibiting apoptosis. When compared with contralateral eyes treated with phosphate-buffered saline, intravitreal administration of E-LPs protected against RGC loss in glutamate aspartate transporter-deficient mice, a model of normal tension glaucoma that causes glaucomatous optic neuropathy without elevation of intraocular pressure. Although the presence of ?2-macroglobulin, another ligand of the low density lipoprotein receptor-related protein 1, interfered with the neuroprotective effect of E-LPs against glutamate-induced neurotoxicity, the addition of E-LPs overcame the inhibitory effect of ?2-macroglobulin. These findings may provide a potential therapeutic strategy for normal tension glaucoma by an LRP1-mediated pathway. PMID:22674573

Hayashi, Hideki; Eguchi, Yuko; Fukuchi-Nakaishi, Yuko; Takeya, Motohiro; Nakagata, Naomi; Tanaka, Kohichi; Vance, Jean E.; Tanihara, Hidenobu



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



Dietary modifications of low-density lipoprotein fatty acids in humans: their effect on low-density lipoprotein-fibroblast interactions.  


The chemical composition and metabolism of low-density lipoproteins (LDLs) in a population of Benedictine nuns were studied after 5-month periods during which the predominant dietary fats were sunflower oil, fluid of palm, peanut oil, milk fats, low erucic acid rapeseed (LEAR) oil, corn oil, olive oil, soybean oil. The population was divided into three groups. The control group (C) included 12 subjects selected at random by taking 2 subjects per age pool among those with plasma cholesterol less than 230 mg/dl. Groups H1 and H2 were selected in the same way among those with plasma cholesterol less than 230 mg/dl. Groups H1 and H2 comprised 6 subjects and differed from each other in the amount of plasma cholesteryl esters, i.e., below and above the mean value of group C. Changes in LDL composition, according to the dietary fat, were associated with changes in LDL catabolism studied in fibroblast cultures, but no significant differences were found between the three groups. PMID:3709035

Baudet, M F; Esteva, O; Lasserre, M; Jacotot, B



Patients with early rheumatoid arthritis exhibit elevated autoantibody titers against mildly oxidized low-density lipoprotein and exhibit decreased activity of the lipoprotein-associated phospholipase A2  

PubMed Central

Rheumatoid arthritis is a chronic inflammatory disease, associated with an excess of cardiovascular morbidity and mortality due to accelerated atherosclerosis. Oxidized low-density lipoprotein (oxLDL), the antibodies against oxLDL and the lipoprotein-associated phospholipase A2 (Lp-PLA2) may play important roles in inflammation and atherosclerosis. We investigated the plasma levels of oxLDL and Lp-PLA2 activity as well as the autoantibody titers against mildly oxLDL in patients with early rheumatoid arthritis (ERA). The long-term effects of immunointervention on these parameters in patients with active disease were also determined. Fifty-eight ERA patients who met the American College of Rheumatology criteria were included in the study. Patients were treated with methotrexate and prednisone. Sixty-three apparently healthy volunteers also participated in the study and served as controls. Three different types of mildly oxLDL were prepared at the end of the lag, propagation and decomposition phases of oxidation. The serum autoantibody titers of the IgG type against all types of oxLDL were determined by an ELISA method. The plasma levels of oxLDL and the Lp-PLA2 activity were determined by an ELISA method and by the trichloroacetic acid precipitation procedure, respectively. At baseline, ERA patients exhibited elevated autoantibody titers against all types of mildly oxLDL as well as low activity of the total plasma Lp-PLA2 and the Lp-PLA2 associated with the high-density lipoprotein, compared with controls. Multivariate regression analysis showed that the elevated autoantibody titers towards oxLDL at the end of the decomposition phase of oxidation and the low plasma Lp-PLA2 activity are independently associated with ERA. After immunointervention autoantibody titers against all types of oxLDL were decreased in parallel to the increase in high-density lipoprotein-cholesterol and high-density lipoprotein-Lp-PLA2 activity. We conclude that elevated autoantibody titers against oxLDL at the end of the decomposition phase of oxidation and low plasma Lp-PLA2 activity are feature characteristics of patients with ERA, suggesting an important role of these parameters in the pathophysiology of ERA as well as in the accelerated atherosclerosis observed in these patients. PMID:17326817

Lourida, Evangelia S; Georgiadis, Athanasios N; Papavasiliou, Eleni C; Papathanasiou, Athanasios I; Drosos, Alexandros A; Tselepis, Alexandros D



Model of human low-density lipoprotein and bound receptor based on CryoEM  

PubMed Central

Human plasma low-density lipoproteins (LDL), a risk factor for cardiovascular disease, transfer cholesterol from plasma to liver cells via the LDL receptor (LDLr). Here, we report the structures of LDL and its complex with the LDL receptor extracellular domain (LDL·LDLr) at extracellular pH determined by cryoEM. Difference imaging between LDL·LDLr and LDL localizes the site of LDLr bound to its ligand. The structural features revealed from the cryoEM map lead to a juxtaposed stacking model of cholesteryl esters (CEs). High density in the outer shell identifies protein-rich regions that can be accounted for by a single apolipoprotein (apo B-100, 500 kDa) leading to a model for the distribution of its ?-helix and ?-sheet rich domains across the surface. The structural relationship between the apo B-100 and CEs appears to dictate the structural stability and function of normal LDL. PMID:20080547

Ren, Gang; Rudenko, Gabby; Ludtke, Steven J.; Deisenhofer, Johann; Chiu, Wah; Pownall, Henry J.



The complex fate in plasma of gadolinium incorporated into high-density lipoproteins used for magnetic imaging of atherosclerotic plaques.  


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



Underappreciated opportunities for high-density lipoprotein particles in risk stratification and potential targets of therapy.  


The inverse relationship between high-density lipoprotein cholesterol (HDL-C) concentrations and coronary heart disease risk is well established. As a result, in recent years there have been significant resources focused on identifying therapies that raise HDL-C and ultimately reduce cardiovascular events. Unfortunately, a number of trials aimed at increasing HDL-C have failed to show improved outcomes, and hence, have cast doubt on the importance of HDL-C as a therapeutic target. HDL-C, however, is only one measure of HDL. HDL levels can also been estimated by quantifying apolipoprotein A-I (apoA-I) levels using enzyme immunoassay or by measuring HDL particle number (HDL-P) using nuclear magnetic resonance spectroscopy (NMR) or ion mobility. While these surrogate measures are correlated, they are not comparable. Lipoprotein-altering therapies have been shown to have different effects on HDL-C, apoA-I and HDL-P and several studies have demonstrated that HDL-P is a stronger predictor of coronary heart disease risk than HDL-C and/or apoA-I. This paper will review available evidence supporting the use of HDL-P as the biomarker of choice to assess the contribution of HDL to cardiovascular risk and as the primary goal of HDL-raising therapies. PMID:25702642

Rosenson, Robert S; Davidson, Michael H; Le, Ngoc-Anh; Burkle, Jaime; Pourfarzib, Ray



Optical Characterization of Europium Tetracycline Complex in the presence of Low Density Lipoprotein and its Applications  

NASA Astrophysics Data System (ADS)

Development of native Low Density Lipoprotein (LDL) biosensors is of great importance in clinical analysis because the LDL concentration, which is the main carrier of cholesterol, in the plasma, is a fundamental parameter for the prevention and diagnosis of a number of clinical disorders such as heart disease, hypertension and atherosclerosis. The optical properties of the Europium-Tetracycline Complex (EuTc) were investigated for the solutions containing LDL in their compositions. In this paper we show an enhancement in the europium luminescence of EuTc complex in the presence of LDL. The time-resolved fluorescence spectroscopy experimental results of the pure EuTc sample and samples with LDL (EuTc:LDL) reveal an increase in the europium emission lifetime in the lipoprotein-doped samples with respect to the pure EuTc sample. A calibration curve, reasonably well described by a linear function between 0 and 3 mg/mL of LDL, was obtained. The obtained limit of detection was 0.23 mg/mL. Sixteen blood plasma samples all of them contend approximately 90 mg/dL of LDL were studied and the LDL concentrations were calculated with our method. The average LDL concentration obtained was 94 mg/dL. The results show that the EuTc complex can be used as a sensor to determine LDL with fast response, compact design, and reproducible results.

de Oliveira Silva, Flávia Rodrigues; Monteiro, Andrea Moreira; Neto, Antônio M. Figueiredo; Gidlund, Magnus A.; Gomes, Laércio; Junior, Nilson Dias Vieira; Courrol, Lilia Coronato



Translation of two aggregated low-density lipoproteins within blood plasma: a mathematical model.  


Arteriosclerosis is a disease in which the artery walls get thicker and harder. Atherosclerosis is a specific form of arteriosclerosis which allows less blood to travel through the artery and increases blood pressure. Low-density lipoproteins (LDLs) and their ability to aggregate are important in atherosclerosis. In the present study we develop a mathematical model that describes the translation of two aggregated LDSs through blood plasma. We model the two aggregated LDLs as an inverted oblate spheroid and the flow as a creeping steady incompressible axisymmetric one. The mathematical tools that we used are the Kelvin inversion and the semi-separation of variables in the spheroidal coordinate systems. The stream function is given as a series expansion of even order terms of combinations of Gegenbauer functions of angular and radial dependence. The analytical solution is expected to give insight into the study of the various chemical precipitation methods used for the precipitation of lipoproteins, as this is the first step for the measurement of their concentration within blood plasma. PMID:25417024

Hadjinicolaou, Maria; Protopapas, Eleftherios



Evidence for low-density lipoprotein receptor-mediated uptake of benzoporphyrin derivative.  

PubMed Central

Plasma lipoproteins, such as low-density lipoprotein (LDL), have been proposed to enhance the delivery of hydrophobic photosensitisers to malignant tissue since tumour cells have been shown to have increased numbers of LDL receptors. We have investigated the role of this receptor in the cellular accumulation of the photosensitiser benzoporphyrin derivative (BPD). We observed that: (1) [14C]BPD-LDL accumulation by LDL receptor-negative fibroblast cell lines was insignificant compared with normal cell lines; (2) there was no evidence that BPD dissociated from LDL during incubation with the cells; and (3) chemical acetylation of LDL markedly decreased the uptake of [14C]BPD-LDL. We conclude, therefore, that virtually all of the photosensitiser accumulated by the cells was due to specific binding and internalisation via the LDL receptor. Subsequent in vivo studies in M-1 (methylcholanthrene-induced rhabdomyosarcoma) tumour-bearing DBA/2J mice showed that tumour accumulation of BPD associated with native LDL was significantly (P < 0.01) enhanced over that of acetyl-LDL-associated BPD. These results indicate that the LDL receptor is responsible for the accumulation of LDL-associated BPD both in vitro and in vivo. Thus, utilisation of this delivery system may provide for improvements in photodynamic therapy in clinical practice. PMID:8180011

Allison, B. A.; Pritchard, P. H.; Levy, J. G.



Gold Nanocrystal Labeling Allows Low Density Lipoprotein Imaging From The Subcellular To Macroscopic Level  

PubMed Central

Low density lipoprotein (LDL) plays a critical role in cholesterol transport and is closely linked to the progression of several diseases. This motivates the development of methods to study LDL behavior from the microscopic to whole-body level. We have developed an approach to efficiently load LDL with a range of diagnostically active nanocrystals or hydrophobic agents. We performed focused experiments on LDL labeled with gold nanocrystals (Au-LDL). The labeling procedure had minimal effect on LDL size, morphology or composition. Biological function was found to be maintained from both in vitro and in vivo experiments. Tumor bearing mice were injected intravenously with LDL, DiR-LDL, Au-LDL or a gold-loaded nanoemulsion. LDL accumulation in the tumors was detected with whole body imaging methods, such as computed tomography (CT), spectral CT and fluorescence imaging. Cellular localization was studied with transmission electron microscopy (TEM) and fluorescence techniques. In conclusion, this LDL labeling procedure should permit the study of lipoprotein biointeractions in unprecedented detail. PMID:24127782

Allijn, Iris E.; Leong, Wei; Tang, Jun; Gianella, Anita; Mieszawska, Aneta J.; Fay, Francois; Ma, Ge; Russell, Stewart; Callo, Catherine B.; Gordon, Ronald E.; Korkmaz, Emine; Post, Jan Andries; Zhao, Yiming; Gerritsen, Hans C.; Thran, Axel; Proksa, Roland; Daerr, Heiner; Storm, Gert; Fuster, Valentin; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J.M.



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 Lipoprotein Increases the Uptake of Oxidized Low Density Lipoprotein via PPAR?/CD36 Pathway in Inflammatory Adipocytes  

PubMed Central

Aim: Previous studies have demonstrated that the dysregulated-secretion of adipokines by adipocytes may contribute to obesity-associated atherosclerosis (As) and high density lipoprotein (HDL) may protect against atherogenesis through multiple pathways. This study was to explore the effect of HDL on the oxLDL uptake in inflammatory adipocytes stimulated by endotoxin lipopolysaccharide (LPS) and the possible mechanism. Methods and Results: 3T3-L1 adipocytes were cultured and induced to differentiation and maturation. Acute inflammation in adipocytes was induced by LPS (100 ng/ml) for 6 hours. The adipocytes were pretreated with HDL in various concentrations (10, 50, 100 ?g/ml) for 16 hours or with specific PPAR? antagonist (GW9662, 10 ?M) or agonist (Rosiglitazone, 10 ?M) for 30 min before administration of LPS. The results showed that LPS significantly increased the release of inflammation-related adipokines, such as monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), tumor necrosis factor-alpha (TNF-?), interleukin (IL)-8 and IL-6, while decreasing the release of leptin and adiponectin. Meanwhile, LPS reduced the uptake and degradation of 125I-oxLDL, and down-regulated the expression of PPAR? and CD36. Pretreatment with HDL dose-dependently affected the release of IL-8 and IL-6 and the reduced uptake and degradation of oxLDL of adipocytes stimulated by LPS, accompanied with marked upregulation of PPAR? and CD36 expression. Pretreatment with GW9662 markedly inhibited the upregulation of CD36 expression mediated by HDL (100 ?g/ml), while the effects of Rosiglitazone were opposite to GW9662. Conclusions: HDL may increase oxLDL uptake of inflammatory adipocytes stimulated by LPS via upregulation of PPAR?/CD36 pathway, which may be a new mechanism of anti-atherosclerosis mediated by HDL. PMID:25678844

Zhong, Qiaoqing; Zhao, Shuiping; Yu, Bilian; Wang, Xing; Matyal, Robina; Li, Yunping; Jiang, Zhisheng



Magnetic Resonance Imaging Detection of Tumor Cells by Targeting Low-Density Lipoprotein Receptors with Gd-Loaded Low-Density Lipoprotein Particles1  

PubMed Central

Gd-DO3A-diph and Gd-AAZTAC17 are lipophilic magnetic resonance imaging (MRI) agents that display high affinity for low-density lipoprotein (LDL) particles. However, on binding to LDL, Gd-DO3A-diph shows a decreased hydration that results in a lower enhancement of water proton relaxation rate. Conversely, Gd-AAZTAC17 displays a strong relaxation enhancement at the imaging fields. Each LDL particle can load up to 100 and 400 UNITS of Gd-DO3A-diph and Gd-AAZTAC17, respectively. Their LDL adducts are taken up by human hepatoblastoma G2 (HepG2) and melanoma B16 tumor cells when added to the incubation medium. T1 measurements of the labeled cells indicate that Gd-AAZTAC17 is significantly more efficient than Gd-DO3A-diph. Furthermore, it has been found that HepG2 hepatoma cells can internalize higher amounts of Gd-AAZTAC17 than B16 cells and the involvement of LDL receptors (LDLRs) has been demonstrated in competition assays with free LDL. Gd-AAZTAC17/LDL adduct proved to be an efficient probe in the magnetic resonance (MR) visualization of subcutaneous tumors in animal models obtained by injecting B16 melanoma cells into the right flank of mice. Finally, confocal microscopy validation of the distribution of LDL-based probes in the tumor has been obtained by doping the Gd-AAZTAC17/LDL adduct with a fluorescent phospholipid moiety. PMID:18084612

Crich, Simonetta Geninatti; Lanzardo, Stefania; Alberti, Diego; Belfiore, Simona; Ciampa, Anna; Giovenzana, Giovanni B; Lovazzano, Clara; Pagliarin, Roberto; Aime, Silvio



Long-term ethanol consumption impairs reverse cholesterol transport function of high-density lipoproteins by depleting high-density lipoprotein sphingomyelin both in rats and in humans  

PubMed Central

Moderate alcohol consumption has been linked to lower incidence of coronary artery disease due to increased plasma high-density lipoprotein (HDL), whereas heavy drinking has the opposite effect. Because of the crucial role of HDL in reverse cholesterol transport and positive correlation of HDL sphingomyelin (SM) content with cholesterol efflux, we have compared HDL SM content with its reverse cholesterol transport capacity both in rats fed ethanol on long-term basis and alcoholic individuals. In rats, SM HDL content was decreased in the ethanol group (?15.4%, P < .01) with a concomitant efflux decrease (?21.0%, P < .01) compared to that in controls. Similarly, HDL from the ethanol group, when compared with HDL from the control group, exhibited 13.8% (P < .05) less cholesterol uptake with control-group hepatocytes and 35.0% (P < .05) less cholesterol uptake with ethanol-group hepatocytes. Conversely, hepatocytes from the ethanol group, when compared with hepatocytes from the control group, exhibited 31.0% (P < .01) less cholesterol uptake with control-group HDL and 48.0% (P < .01) less with ethanol-group HDL. In humans, SM content in plasma HDL was also decreased in chronically alcoholic individuals without liver disease (?51.5%, P < .01) and in chronically alcoholic individuals with liver disease (?51.3%, P < .01), compared with nondrinkers. Concomitantly, in alcoholic individuals without liver disease, both efflux and uptake were decreased by 83.0% and 54.0% (P < .01), respectively, and in chronically alcoholic individuals with liver disease by 84.0% and 61.0% (P < .01), respectively, compared with nondrinkers. Based on these findings, we conclude that long-term ethanol consumption significantly impairs not only cholesterol efflux function of HDL by decreasing its SM content but also cholesterol uptake by affecting presumably hepatocyte receptors for HDL. PMID:17570257

Marmillot, Philippe; Munoz, Jennifer; Patel, Sanket; Garige, Mamatha; Rosse, Richard B.; Lakshman, M. Raj



High-density lipoprotein subfractions: current views and clinical practice applications.  


High-density lipoprotein (HDL) is astonishingly complex, but the de facto standard for its measurement has been remarkably simple: total cholesterol content. It is time to prioritize higher-resolution HDL measurement techniques that capture better the biologically and clinically important characteristics of HDL. Scientific advances have ushered in a new era in which we view HDL in terms of its subfractions, particle structure, metabolism, and functional integration of its proteome and lipidome. HDL subfractions appear to be associated with function. In general, smaller, denser HDL3 is more tightly linked to favorable atheroprotective functions and clinical outcomes. Techniques to measure the cholesterol content or particle concentrations of HDL subfractions are available clinically. In the future, we anticipate subfractionating HDL based on its functional properties. PMID:24931711

Martin, Seth S; Jones, Steven R; Toth, Peter P



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

PubMed Central

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

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



Effect of alcohol intake on high-density lipoprotein cholesterol levels in runners and inactive men.  


Plasma high-density lipoprotein cholesterol (HDLC) level was measured before and after alcohol abstinence and after resumption of a controlled alcohol dose in 16 marathon runners, 15 joggers, and 13 inactive men. A three-week period of abstinence resulted in a significant decrease in HDLC concentration in the inactive men (49.8 to 41.8 mg/dL). Three weeks of alcohol consumption (1,065 mL of beer per day) produced a significant increase in HDLC level to 50.9 mg/dL. No change in HDLC level was found for the marathon group or the joggers during abstinence or three weeks of alcohol intake. The consumption of alcohol in moderation seems to be associated with increased HDLC levels in inactive men but not in men who engage in regular running or jogging. PMID:6823027

Hartung, G H; Foreyt, J P; Mitchell, R E; Mitchell, J G; Reeves, R S; Gotto, A M



Statin-mediated low-density lipoprotein lowering in chronic congestive heart failure.  


Many theories and clinical trials have attempted to address the effect of low-density lipoprotein (LDL) lowering in chronic congestive heart failure (CHF). The current evidence suggests that there is no convincing reason for administering statins to patients with nonischemic heart failure. Although they do not reduce the mortality rate, statins reduce LDL cholesterol and may provide some benefit to patients with ischemic heart failure. In contrast, some authors believe that statin therapy may actually worsen outcomes in patients with CHF, especially if there is excessive reduction in LDL cholesterol. This review discusses the theories attempting to link the adverse effects of statin-mediated LDL lowering in CHF to increased levels of endotoxin or reduced levels of coenzyme Q10. In addition, the 2 largest randomized, double-blind, placebo-controlled clinical trials (CORONA and GISSI-HF) were discussed. It is clear that more trials are needed to definitely ascertain the effect of statins on CHF. PMID:23154655

Kosmas, Constantine E; Alkhawam, Hassan; El-Hunjul, Mohammed; Wagman, Gabriel; Kahn, Mark R; Grady, Kathleen M; Vittorio, Timothy J



Interrelatedness between C-reactive protein and oxidized low-density lipoprotein.  


C-reactive protein (CRP) is a marker of inflammation. Atherosclerosis is now recognized as inflammatory disease, and it seems that CRP directly contributes to atherogenesis. Oxidation of low-density lipoprotein (LDL) molecule increases the uptake of lipid products by macrophages leading to cholesterol accumulation and subsequent foam cell formation. The elevated levels of high sensitivity CRP (hsCRP) and oxidized LDL (OxLDL) in the blood were found to be associated with cardiovascular diseases (CVD). In this review, we highlighted the evidence that CRP and OxLDL are involved in interrelated (patho) physiological pathways. The findings on association between hsCRP and OxLDL in the clinical setting will be also summarized. PMID:25010779

Obradovic, Milan M; Trpkovic, Andreja; Bajic, Vladan; Soskic, Sanja; Jovanovic, Aleksandra; Stanimirovic, Julijana; Panic, Milos; Isenovic, Esma R



Low-density-lipoprotein receptors in human fibroblasts are not degraded in lysosomes.  

PubMed Central

The rate of degradation of low-density-lipoprotein (LDL) receptors was measured in cultured human skin fibroblasts by [35S]methionine pulse-chase experiments. The half-life of LDL receptors was unaltered by inclusion of LDL in the medium (t1/2 11 h). Neither lysosomotropic inhibitors (chloroquine or NH4Cl) nor leupeptin inhibited the rate of receptor degradation in the absence of ligand. In cells incubated at 18 degrees C to inhibit the delivery of internalized ligands from endocytic vesicles to lysosomes, receptor degradation continued, but at the expected rate of about six times lower than that at 37 degrees C. Mutant LDL receptors defective in internalization were degraded at the same rate as normal receptors, suggesting that receptor internalization and recycling are not required for basal turnover. We conclude that the rate-limiting steps for, and probably the whole pathway of, degradation of normal LDL receptors does not take place in lysosomes. PMID:2803276

Casciola, L A; Grant, K I; Gevers, W; Coetzee, G A; van der Westhuyzen, D R



Anticipatory Role of High Density Lipoprotein and Endothelial Dysfunction: An Overview  

PubMed Central

High Density Lipoprotein (HDL) has been witnessed to possess a range of different functions that contribute to its atheroprotective effects. These functions are: the promotion of macrophage cholesterol efflux, reverse cholesterol transport, anti-inflammatory, anti-thrombotic, anti-apoptotic, pro-fibrinolytic and anti-oxidative functions. Paraoxonase 1 (PON1) is an HDL associated enzyme esterase/homocysteinethiolactonase that contributes to the anti-oxidant and anti-atherosclerotic capabilities of HDL. PON1 is directly involved in the etiopathogenesis of atherosclerosis through the modulation of nitric oxide (NO) bioavailability. The aim of this review is to summarize the role of HDL on endothelial homeostasis, and also to describe the recently characterized molecular pathways involved. PMID:25598849

Eren, Esin; Y?lmaz, Necat; Aydin, Ozgur; Ellida?, Hamit Y



A mathematical model for the blood plasma flow around two aggregated low-density lipoproteins.  


The rheological behaviour of low-density lipoprotein (LDL) particles within the blood plasma and their role in atherogenesis, as well as their ability to aggregate under certain circumstances, is the subject of many clinical tests and theoretical studies aiming at the prevention of atherosclerosis. In the present study we develop a mathematical model that describes the flow of the blood plasma around two aggregated LDLs. We consider the flow as a creeping steady incompressible axisymmetric one, while the two aggregated LDLs are described by an inverted oblate spheroid. The mathematical methods of Kelvin inversion and the semi-separation of variables are employed and analytical expressions for the stream function are derived. These expressions are expected to be useful for further model developing and screening as well as the theoretical justification and validation of laboratory results. PMID:25417023

Hadjinicolaou, Maria



Low-density lipoprotein cholesterol lowering therapies: what is on the horizon?  


Elevated low-density lipoprotein cholesterol (LDL-C) levels are associated with an increased risk for cardiovascular disease (CVD). Statins have been the cornerstone of lipid therapy to lower LDL-C for the past two decades, but despite significant clinical efficacy in a majority of patients, a large residual risk remains for the development of initial or recurrent atherosclerotic CVD. In addition, owing to the side-effects, a significant percentage of patients cannot tolerate any statin dose or a high enough statin dose. Thus, novel therapeutic agents are currently being developed to lower LDL-C levels further. This review will highlight these novel therapeutic agents including antisense oligonucleotides focused on apolipoprotein B, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and microsomal triglyceride transfer protein inhibitors. For each therapeutic class, an overview of mechanism of action, pharmacokinetic data, and efficacy/safety evidence will be discussed. PMID:25379719

Gadi, Ramprasad; Figueredo, Vincent M



Inhibition of human low-density lipoprotein oxidation in vitro by ginger extracts.  


Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in atherosclerotic plaque formation. Currently, there is a renewed interest in ginger because of its antioxidants and cardioprotective properties. The effects of ethanol, methanol, ethyl acetate, and hexane solvent extracts of ginger and pure major ginger constituents on Cu(2+)-induced oxidation of human LDL in vitro were examined. The LDL oxidation inhibition by ethanol, methanol, ethyl acetate, and hexane extracts of ginger was 71%, 76%, 67%, and 67%, respectively, at their optimum extraction conditions. Inhibition of LDL oxidation by water extracts of ginger, which was prepared by ultrasonic-assisted extraction conditions of 52°C for 15 min, was about 43%. Phenolic bioactives of ginger-6-gingerols, 8-gingerols, 10-gingerols, and 6-shogaol-seem to be strong inhibitors of Cu(+2)-induced LDL oxidation. Overall, ginger extracts, including the water extract possess the antioxidant activities to inhibit human LDL oxidation in vitro. PMID:24404979

Gunathilake, K D Prasanna P; Rupasinghe, H P Vasantha



[A simple method for quantification of modified low-density lipoproteins].  


A simple method for quantification of modified low-density lipoproteins (mLDL) in the blood serum containing 8.9% polyvinylpyrrolidone solution 12600 +/- 2700 has been developed. The results show that 10 min incubation of serum in a buffer containing 8.9% PVP leads to complete aggregation mLDL. Atherogenicity of aggregated mLDLs is experimentally confirmed by two independent tests (mLDLs bind and activate the complement system of a guinea pig (pro-inflammatory effect) and cause platelet hyperaggregation (thrombogenic effect)). The proposed method is simple and involves only two steps: mixing the serum with a solution of PVP and recording the turbidity. The method allows to register the presence of mLDL directly in serum without its prior fractionation. PMID:22708414

Sho?bonov, B B; Baronets, V Iu; Panchenko, L F; Pal'tsyn, A A; Kubatiev, A A



Composition of plasma and nascent very low density lipoprotein from perfused livers of hypercholesterolemic squirrel monkeys.  


The composition of circulating very low density lipoprotein (VLDL) was compared with the composition and secretion of nascent VLDL from perfused livers of squirrel monkeys that were fed unsaturated or saturated fat diets to elicit different degrees of plasma hypercholesterolemia. All squirrel monkeys studied had cholesteryl ester-rich plasma VLDL, although greater enrichment occurred in hypercholesterolemic animals fed saturated fat. Livers from hypercholesterolemic animals were capable of secreting VLDL particles enriched in cholesteryl ester, suggesting hepatic origin for a portion of this circulating lipid moiety. Total VLDL lipid, but not protein output by perfused livers of hypercholesterolemic monkeys, was greater than that by livers from hypocholesterolemic animals. These results indicate that saturated fat-induced hypercholesterolemia is associated with changes in the composition of hepatic VLDL in the squirrel monkey. PMID:7432101

Nicolosi, R J; Hayes, K C



Relationship between paraoxonase 1 activity and high density lipoprotein concentration during naturally occurring babesiosis in dogs.  


Paraoxonase 1 (PON1) is a negative acute phase protein bound to high density lipoproteins (HDL) and during the acute phase response (APR) protects HDL from peroxidation. The aim of this study was to assess the relationship between PON1 and HDL in canine babesiosis, a disease characterized by oxidative damages and by an APR. PON1, HDL and C-reactive protein (CRP), were measured in blood collected from 15 controls and 29 dogs with babesiosis sampled at admission, and on days 1 and 7 after treatment. At admission, PON1 and HDL were significantly lower in affected dogs. HDL concentration increased at day 1 while PON1 increased and CRP decreased at day 7. This suggests that the decrease of PON1 at admission is in part due to an increased consumption, the decreased HDL may depend on lipid peroxidation and its rapid increase after treatment may depend on the antioxidant activity of PON1. PMID:25104322

Rossi, G; Kuleš, J; Rafaj, R Bari?; Mrljak, V; Lauzi, S; Giordano, A; Paltrinieri, S



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



Green tea polyphenols (flavan 3-ols) prevent oxidative modification of low density lipoproteins: an ex vivo study in humans  

Microsoft Academic Search

Oxidation of low density lipoprotein (LDL) plays crucial roles in atherogenesis. We previously reported that green tea polyphenols (flavan 3-ols), especially epigallocatechingallate (EGCg) and epicatechingallate, exerted potent inhibitory effects on LDL oxidation in vitro. To examine whether intake of green tea polyphenols renders LDL resistant to ex vivo oxidation in humans, 22 male volunteers aged between 22 and 32 years

Yukiko Miura; Tsuyoshi Chiba; Shinji Miura; Isao Tomita; Keizo Umegaki; Masahiko Ikeda; Takako Tomita



Plasma matrix metalloproteinases, low density lipoprotein oxidisability and soluble adhesion molecules after a glucose load in Type 2 diabetes  

Microsoft Academic Search

BACKGROUND: Acute hyperglycaemia is an independent cardiovascular risk factor in Type 2 diabetes which may be mediated through increased oxidative damage to plasma low density lipoprotein, and in vitro, high glucose concentrations promote proatherogenic adhesion molecule expression and matrix metalloproteinase expression. METHODS: We examined these atherogenic risk markers in 21 subjects with Type 2 diabetes and 20 controls during an

Mike Sampson; Isabel Davies; Jelena Gavrilovic; Brendan Sussams; Jackie Brown; Sian Astley; David A Hughes



Antioxidant activity of phenolic acids and esters present in red wine on human Low-Density Lipoproteins  

Microsoft Academic Search

To evaluate the antioxidant activity of different phenolic acids and their esters, three types of experiments have been used. Electron paramagnetic resonance (EPR) quantitative analysis was carried out using the acetaldehyde\\/xanthine oxidase system and Fenton's reaction to generate superoxide and hydroxyl radicals, respectively. In a second test, hydroperoxides generated by Cu2+-catalysed oxidation of low density lipoproteins (LDL) were quantified by

P. Urizzi; M.-C. Monje; J.-P. Souchard; A. Abella; J. Chalas; A. Lindenbaum; L. Vergnes; S. Labidalle; F. Nepveu



Oxidized Low Density Lipoprotein Induces Differentiation and Adhesion of Human Monocytes and the Monocytic Cell Line U937  

Microsoft Academic Search

Hypercholesterolemia is a major risk factor for development of atherosclerosis. In experimental animals fed a high-cholesterol diet, monocytes adhere to the arterial endothelium and penetrate into the intima where they differentiate into macrophages and ingest lipids thus giving rise to fatty streaks, the earliest type of atherosclerotic plaque. Macrophages express few receptors for normal low density lipo-protein (LDL) but can

Johan Frostegard; Jan Nilsson; Anders Haegerstrand; Anders Hamsten; Hans Wigzell; Magnus Gidlund



Lysophosphatidylcholine plays an essential role in the mitogenic effect of oxidized low density lipoprotein on murine macrophages.  


We previously demonstrated that the growth of starch-induced murine macrophages was stimulated by modified low density lipoproteins, such as oxidized low density lipoprotein (Ox-LDL) and acetylated low density lipoprotein (acetyl-LDL), and that the mitogenic effect of Ox-LDL was much greater than that of acetyl-LDL (Yui, S., Sasaki, T., Miyazaki, A., Horiuchi, S., and Yamazaki, M. (1993) Arterioscler. Thromb. 13, 331-337). The present study was undertaken to elucidate the factor(s) that are involved in this growth-stimulating effect of Ox-LDL. The growth-stimulating effect of acetyl-LDL on murine resident macrophages was negligibly weak compared with that of Ox-LDL. However, the treatment of acetyl-LDL with phospholipase A2 led to an increase in lysophosphatidylcholine (lyso-PC) (75% of total phospholipids) and a concomitant increase in the mitogenic activity of acetyl-LDL. In contrast, cell-free incubation of Ox-LDL with high density lipoprotein resulted in a decrease in lyso-PC content and a concomitant loss of growth-stimulating activity. These results suggest that lyso-PC may play an essential role in the mitogenic activity of Ox-LDL. PMID:7989310

Sakai, M; Miyazaki, A; Hakamata, H; Sasaki, T; Yui, S; Yamazaki, M; Shichiri, M; Horiuchi, S



Detection of the low density lipoprotein (LDL) receptor on nitrocellulose paper with colloidal gold-LDL conjugates  

Microsoft Academic Search

Gold-low density lipoprotein (LDL) conjugates were used to detect the LDL receptor on nitrocellulose paper. Solubilized rat liver membrane proteins were subjected to electrophoresis and electroblotted onto nitrocellulose paper. The receptor was then detected as a red band (within 10 min) by overlaying with the LDL conjugates. The coloration was prevented by unlabeled LDL, EDTA, and suramin but not by

Paul Daniel Roach; Max Zollinger; S. P. Nol



Androgen Receptor-Mediated Antagonism of Estrogen-Dependent Low Density Lipoprotein Receptor Transcription in Cultured Hepatocytes  

Microsoft Academic Search

Postmenopausal women receiving hormone replacement therapy have a lower risk of coronary heart disease than women who do not receive hormone treatment. Multiple mechanisms are likely to un- derlie estrogen's cardioprotective action, including lowering of plasma low density lipoprotein (LDL) cholesterol. Using an in vitro system exhibiting normal regulation of LDL receptor (LDLR) gene transcrip- tion, we show that 17b-estradiol




Two mutant low-density-lipoprotein receptors in Afrikaners slowly processed to surface forms exhibiting rapid degradation or functional heterogeneity.  

PubMed Central

Two distinct mutant low-density-lipoprotein receptors in South African Afrikaners exhibit retarded posttranslational processing to mature forms. One mutation gives rise to cell-surface receptors that are subject to abnormally rapid degradation, whereas the other is associated with a functionally heterogeneous surface population degraded at a normal rate. Images Fig. 2. Fig. 3. Fig. 4. PMID:3202825

Fourie, A M; Coetzee, G A; Gevers, W; van der Westhuyzen, D R



Two novel frameshift mutations in the low density lipoprotein receptor gene generated by endogenous sequence-directed mechanisms  

Microsoft Academic Search

DNA samples from 60 unrelated Belgian hypercholesterolemic patients were subjected to heteroduplex analysis of exon 4 of the low density lipoprotein receptor (LDLR) gene. Aberrant mobility bands were detected in 2 patients and the underlying mutations were characterized by DNA sequence analysis. Both mutations, a 19-bp insertion at codon 141 and a 23-bp deletion at codon 168, produce premature stop

Armand V. Peeters; Luc E Van Gaal; Leonora Theart; Elzet Langenhoven; Maritha J. Kotze



Genetic variation at the PCSK9 locus, low density lipoproteins, response to pravastatin and coronary heart disease: results from PROSPER  

Technology Transfer Automated Retrieval System (TEKTRAN)

Caucasian carriers of the T allele at R46L in the proprotein convertase subtilisin/kexin type 9 (PCSK9) locus have been reported to have 15% lower low-density lipoprotein (LDL) cholesterol (C) levels and 47% lower coronary heart disease (CHD) risk. Our objective was to examine two PCSK9 single nucle...


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

E-print Network

of human low density lipoprotein (LDL) particles as delivery system for lipophilic, cytotoxic drugs) and other macromolecules (Duncan, 1992) have been proposed as targeting carriers to deliver cytotoxic drugs for the applicability as drug delivery system Michal Hammel, Peter Laggner, Ruth Prassl * Institute of Biophysics and X

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


Binding of ethyl oleate to low density lipoprotein, phospholipid vesicles, and albumin: a l3C NMR study  

Microsoft Academic Search

Fatty acid ethyl esters (FAEE), esterification products of ethanol and fatty acids, have been implicated as mediators of ethanol-induced organ damage. After ethanol ingestion in humans, FAEE circulate in blood, bound to lipo- proteins and albumin. We have analyzed the binding of ethyl (PC, 99%) oleate (EO) to small unilamellar phospholipid vesicles (SUV), human low density lipoprotein (LDL), and bovine

David A. Bird; Michael Laposata; James A. Hamilton


Collagenase-3 binds to a specific receptor and requires the low density lipoprotein receptor-related protein for internalization  

NASA Technical Reports Server (NTRS)

We have previously identified a specific receptor for collagenase-3 that mediates the binding, internalization, and degradation of this ligand in UMR 106-01 rat osteoblastic osteosarcoma cells. In the present study, we show that collagenase-3 binding is calcium-dependent and occurs in a variety of cell types, including osteoblastic and fibroblastic cells. We also present evidence supporting a two-step mechanism of collagenase-3 binding and internalization involving both a specific collagenase-3 receptor and the low density lipoprotein receptor-related protein. Ligand blot analysis shows that (125)I-collagenase-3 binds specifically to two proteins ( approximately 170 kDa and approximately 600 kDa) present in UMR 106-01 cells. Western blotting identified the 600-kDa protein as the low density lipoprotein receptor-related protein. Our data suggest that the 170-kDa protein is a specific collagenase-3 receptor. Low density lipoprotein receptor-related protein-null mouse embryo fibroblasts bind but fail to internalize collagenase-3, whereas UMR 106-01 and wild-type mouse embryo fibroblasts bind and internalize collagenase-3. Internalization, but not binding, is inhibited by the 39-kDa receptor-associated protein. We conclude that the internalization of collagenase-3 requires the participation of the low density lipoprotein receptor-related protein and propose a model in which the cell surface interaction of this ligand requires a sequential contribution from two receptors, with the collagenase-3 receptor acting as a high affinity primary binding site and the low density lipoprotein receptor-related protein mediating internalization.

Barmina, O. Y.; Walling, H. W.; Fiacco, G. J.; Freije, J. M.; Lopez-Otin, C.; Jeffrey, J. J.; Partridge, N. C.



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



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


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

Corral, Pablo; Schreier, Laura



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



Density profile and cholesterol concentration of serum lipoproteins in experimental animals and human subjects on hypercholesterolaemic diets  

Microsoft Academic Search

1. 1. The density profile of Sudan black stained serum lipoproteins was studied in human subjects and various animal species on diets supplemented with cholesterol.\\u000a\\u000a2. 2. In the animals studied (rabbits, calves, mice, chickens, rats and guinea-pigs), the feeding of cholesterol resulted in an elevation of serum cholesterol levels together with marked changes in the density profile and the

A. H. M. Terpstra



Apolipoprotein A-I structural organization in high density lipoproteins isolated from human plasma  

PubMed Central

High density lipoproteins (HDL) mediate cholesterol transport and protection from cardiovascular disease. Although synthetic HDLs have been studied for 30 years, the structure of human plasma-derived HDL, and its major protein apolipoprotein (apo)A-I, is unknown. We separated normal human HDL into 5 density subfractions and then further isolated those containing predominantly apoA-I (LpA-I). Using cross-linking chemistry and mass spectrometry, we found that apoA-I adopts a structural framework in these particles that closely mirrors that in synthetic HDL. We adapted established structural models for synthetic HDL to generate the first detailed models of authentic human plasma HDL in which apoA-I adopts a symmetrical cage-like structure. The models suggest that HDL particle size is modulated via a twisting motion of the resident apoA-I molecules. This understanding offers insights into how apoA-I structure modulates HDL function and its interactions with other apolipoproteins. PMID:21399642

Huang, Rong; Gangani D. Silva, R. A.; Jerome, W. Gray; Kontush, Anatol; Chapman, M. John; Curtiss, Linda K.; Hodges, Timothy J.; Davidson, W. Sean



ApoE and the role of very low density lipoproteins in adipose tissue inflammation  

Technology Transfer Automated Retrieval System (TEKTRAN)

Our goal was too identify the role of triglyceride-rich lipoproteins and apoE, a major apolipoprotein in triglyceride-rich lipoproteins, in adipose tissue inflammation with high-fat diet induced obesity. Male apoE-/- and C57BL/6J wild-type mice fed high fat diets for 12 weeks were assessed for metab...


Centripetal cholesterol flux to the liver is dictated by events in the peripheral organs and not by the plasma high density lipoprotein or apolipoprotein AI concentration  

Microsoft Academic Search

The major net flux of cholesterol in the intact an- imal or human is from the peripheral organs to the liver. This flux is made up of cholesterol that is either synthesized in these peripheral tissues or taken up as lipoprotein choles- terol. This study investigates whether it is the concentration of apolipoprotein (apo) A-I or high density lipoprotein in

Christopher D. Jolley; Laura A. Woollett; Stephen D. Turley; John M. Dietsch


Mechanisms responsible for hepatic very low density lipoprotein-apoB100 overproduction in Otsuka Long-Evans Tokushima fatty rats  

Technology Transfer Automated Retrieval System (TEKTRAN)

Overproduction of hepatic very low-density lipoprotein (VLDL)1 particles is a major abnormality of lipoprotein dysregulation in type 2 diabetes (T2D). We sought to examine the mechanisms linking systemic/hepatic inflammation associated with insulin resistance and apolipoprotein (apo) B100-containing...


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



Association Between Circulating Oxidized Low-Density Lipoprotein and Incidence of the Metabolic Syndrome  

PubMed Central

Context Experimental data support the hypothesis that oxidized low-density lipoprotein (LDL) is associated with the metabolic syndrome. However, this hypothesis has not been tested in humans. Objective To establish the relation of oxidized LDL with metabolic syndrome in the general community. Design, Setting, and Participants The Coronary Artery Risk Development in Young Adults (CARDIA) study is a population-based, prospective, observational study. We studied 1889 participants who were between the ages of 18 and 30 years at the time of recruitment in 1985 and 1986 and living in 1 of 4 US metropolitan areas (41% African American; 56% women) and were seen both at year 15 (2000–2001, ages 33–45 years) and year 20 examinations (2005–2006). Main Outcome Measure The longitudinal association of oxidized LDL and incident metabolic syndrome. Oxidized LDL was measured with a monoclonal antibody-based enzyme-linked immunosorbent assay. The metabolic syndrome was defined according to the Adult Treatment Panel III of the National Cholesterol Education Program. Results Incident metabolic syndrome was diagnosed at the year 20 follow-up in 12.9% (243 of 1889) of participants who did not have metabolic syndrome at the 15-year followup. The odds ratios (ORs) for incident metabolic syndrome after 5 years' follow-up and adjusted for age, sex, race, study center, cigarette smoking, body mass index, physical activity, and LDL cholesterol levels by quintiles of oxidized LDL were 2.1 (95% confidence interval [CI], 1.1–3.8) for the second quintile (55.4–69.1 U/L); 2.4 (95% CI, 1.3–4.3) for the third quintile (69.2–81.2 U/L); 2.8 (95% CI, 1.5–5.1) for the fourth quintile (81.3–97.3 U/L); and 3.5(95%CI, 1.9–6.6) for the fifth quintile (?97.4 U/L). The adjusted ORs for incidence of dichotomous components of metabolic syndrome in the highest vs the lowest quintile of oxidized LDL were 2.1 (95% CI, 1.2–3.6) for abdominal obesity, 2.4 (95% CI, 1.5–3.8) for high fasting glucose, and 2.1 (95% CI, 1.1–4.0) for high triglycerides. Low-density lipoprotein cholesterol was not associated with incident metabolic syndrome or with any of its components in the fully adjusted model containing oxidized LDL. Conclusion Higher concentration of oxidized LDL was associated with increased incidence of metabolic syndrome overall, as well as its components of abdominal obesity, hyperglycemia, and hypertriglyceridemia. PMID:18492970

Holvoet, Paul; Lee, Duk-Hee; Steffes, Michael; Gross, Myron; Jacobs, David R.



Women have a larger and less atherogenic low density lipoprotein particle size than men.  


Some epidemiological studies have shown that serum total cholesterol increases with age. especially in women. On the other hand, the risk of coronary artery disease is smaller in women than in men. Earlier studies have shown that a small dense low density lipoprotein (LDL) is more atherogenic than a large LDL. We studied LDL size and apolipoprotein E (apo E) phenotypes in premenopausal and postmenopausal women and in men at the same age. In this study 342 subjects participating in a health screening study were examined. There were four subgroups: 40-year-old men (n = 85), 40-year-old women (n = 80), 70-year old men (n = 88) and 70-year-old women (n = 89). In the present study LDL size was larger (P < 0.01) in women (26.39 +/- 0.07 nm) than in men (25.95 +/- 0.07 nm). We found that LDL size correlated highly positively (r = 0.606; P < 0.001) with serum high density lipoprotein (HDL) concentration and inversely with serum triglyceride concentration (r = -0.627; P < 0.001). Measuring serum HDL cholesterol and triglycerides in health screening studies gives information indirectly about LDL size and its atherogenicity. Apo E phenotype was not significantly associated with serum triglycerides, but was associated with LDL size, LDL cholesterol, total cholesterol and HDL cholesterol. In our sample LDL size decreased and LDL cholesterol and total cholesterol increased according to the most prevalent apo E phenotypes in the order E2/3, E3/3, E3/4 and E4/4. Subjects with phenotype apo E4/4 had the smallest LDL size (25.70 +/- 0.19 nm), the highest total cholesterol (6.53 +/- 0.35 mmol/l) and the lowest HDL cholesterol values (1.28 +/- 0.04 mmol/l). We conclude that there was a significant interaction between sex and age in serum total cholesterol which was highest in older women. However, their LDL size was larger and their LDL is less atherogenic. Apo E phenotype had a significant influence on LDL size. PMID:8808495

Nikkilä, M; Pitkäjärvi, T; Koivula, T; Solakivi, T; Lehtimäki, T; Laippala, P; Jokela, H; Lehtomäki, E; Seppä, K; Sillanaukee, P



Lipoprotein lipase (LPL) strongly links native and oxidized low density lipoprotein particles to decorin-coated collagen. Roles for both dimeric and monomeric forms of LPL.  


Low density lipoprotein (LDL) and oxidized LDL are associated with collagen in the arterial intima, where the collagen is coated by the small proteoglycan decorin. When incubated in physiological ionic conditions, decorin-coated collagen bound only small amounts of native and oxidized LDL, the interaction being weak. When decorin-coated collagen was first allowed to bind lipoprotein lipase (LPL), binding of native and oxidized LDL increased dramatically (23- and 7-fold, respectively). This increase depended on strong interactions between LPL that was bound to the glycosaminoglycan chains of the collagen-bound decorin and native and oxidized LDL (kDa 12 and 5.9 nM, respectively). To distinguish between binding to monomeric (inactive) and dimeric (catalytically active) forms of LPL, affinity chromatography on heparin columns was conducted, which showed that native LDL bound to the monomeric LPL, whereas oxidized LDL, irrespective of the type of modification (Cu(2+), 2, 2'-azobis(2-amidinopropane)hydrochloride, hypochlorite, or soybean 15-lipoxygenase), bound preferably to dimeric LPL. However, catalytic activity of LPL was not required for binding to oxidized LDL. Finally, immunohistochemistry of atherosclerotic lesions of human coronary arteries revealed specific areas in which LDL, LPL, decorin, and collagen type I were present. The results suggest that LPL can retain LDL in atherosclerotic lesions along decorin-coated collagen fibers. PMID:10681554

Pentikäinen, M O; Oörni, K; Kovanen, P T



Increased expression of apolipoprotein E in transgenic rabbits results in reduced levels of very low density lipoproteins and an accumulation of low density lipoproteins in plasma.  


Transgenic rabbits expressing human apo E3 were generated to investigate mechanisms by which apo E modulates plasma lipoprotein metabolism. Compared with nontransgenic littermates expressing approximately 3 mg/dl of endogenous rabbit apo E, male transgenic rabbits expressing approximately 13 mg/dl of human apo E had a 35% decrease in total plasma triglycerides that was due to a reduction in VLDL levels and an absence of large VLDL. With its greater content of apo E, transgenic VLDL had an increased binding affinity for the LDL receptor in vitro, and injected chylomicrons were cleared more rapidly by the liver in transgenic rabbits. In contrast to triglyceride changes, transgenic rabbits had a 70% increase in plasma cholesterol levels due to an accumulation of LDL and apo E-rich HDL. Transgenic and control LDL had the same binding affinity for the LDL receptor. Both transgenic and control rabbits had similar LDL receptor levels, but intravenously injected human LDL were cleared more slowly in transgenic rabbits than in controls. Changes in lipoprotein lipolysis did not contribute to the accumulation of LDL or the reduction in VLDL levels. These observations suggest that the increased content of apo E3 on triglyceride-rich remnant lipoproteins in transgenic rabbits confers a greater affinity for cell surface receptors, thereby increasing remnant clearance from plasma. The apo E-rich large remnants appear to compete more effectively than LDL for receptor-mediated binding and clearance, resulting in delayed clearance and the accumulation of LDL in plasma. PMID:9593771

Fan, J; Ji, Z S; Huang, Y; de Silva, H; Sanan, D; Mahley, R W; Innerarity, T L; Taylor, J M



Alpha-adrenergic suppression of very-low-density-lipoprotein triacylglycerol secretion by isolated rat hepatocytes.  

PubMed Central

The effect of adrenaline on triacylglycerol synthesis and secretion was examined in isolated rat hepatocytes. Cells were incubated with 0.5 mM-[1-14C]oleate, and the accumulation of triacylglycerol and [14C]triacylglycerol was measured in the incubation medium. Triacylglycerol appearing in the medium was present in a form with properties similar to very-low-density lipoproteins. Triacylglycerol, [14C]triacylglycerol and [14C]phospholipid contents of hepatocytes were also determined. Addition of 10 microM-(-)adrenaline decreased accumulation of glycerolipid in the incubation medium and also decreased cellular [14C]phospholipid content. Prazosin abolished these effects, whereas propranolol did not. The hormone did not affect cellular triacylglycerol content or rates of incorporation of [1-14C]oleate into cell triacylglycerol. The effect of adrenaline on the removal of newly secreted triacylglycerol and the secretion of synthesized glycerolipid was also examined. The catecholamine did not affect rates of removal of newly secreted triacylglycerol. Adrenaline did inhibit the secretion of pre-synthesized lipid by the cells, as assessed by the appearance of radiolabelled triacylglycerol from hepatocytes that had been preincubated with [1,2,3-3H]-glycerol. Adrenaline did not affect rates of fatty acid uptake by hepatocytes, but did stimulate oxidation of [1-14C]oleate, principally to 14CO2. PMID:3355529

Brindle, N P; Ontko, J A



l-Cystathionine Inhibits the Mitochondria-Mediated Macrophage Apoptosis Induced by Oxidized Low Density Lipoprotein  

PubMed Central

This study was designed to investigate the regulatory role of l-cystathionine in human macrophage apoptosis induced by oxidized low density lipoprotein (ox-LDL) and its possible mechanisms. THP-1 cells were induced with phorbol 12-myristate 13-acetate (PMA) and differentiated into macrophages. Macrophages were incubated with ox-LDL after pretreatment with l-cystathionine. Superoxide anion, apoptosis, mitochondrial membrane potential, and mitochondrial permeability transition pore (MPTP) opening were examined. Caspase-9 activities and expression of cleaved caspase-3 were measured. The results showed that compared with control group, ox-LDL treatment significantly promoted superoxide anion generation, release of cytochrome c (cytc) from mitochondrion into cytoplasm, caspase-9 activities, cleavage of caspase-3, and cell apoptosis, in addition to reduced mitochondrial membrane potential as well as increased MPTP opening. However, 0.3 and 1.0 mmol/L l-cystathionine significantly reduced superoxide anion generation, increased mitochondrial membrane potential, and markedly decreased MPTP opening in ox-LDL + l-cystathionine macrophages. Moreover, compared to ox-LDL treated-cells, release of cytc from mitochondrion into cytoplasm, caspase-9 activities, cleavage of caspase-3, and apoptosis levels in l-cystathionine pretreated cells were profoundly attenuated. Taken together, our results suggested that l-cystathionine could antagonize mitochondria-mediated human macrophage apoptosis induced by ox-LDL via inhibition of cytc release and caspase activation. PMID:25514411

Zhu, Mingzhu; Du, Junbao; Chen, Siyao; Liu, Angie Dong; Holmberg, Lukas; Chen, Yonghong; Zhang, Chunyu; Tang, Chaoshu; Jin, Hongfang



Rosiglitazone attenuates atherosclerosis and increases high-density lipoprotein function in atherosclerotic rabbits  

PubMed Central

Rosiglitazone has been found to have anti-atherogenic effects and to increase serum high-density lipoprotein (HDL) cholesterol (HDL-C) levels. However, in vivo studies investigating the regulation of adenosine triphosphate-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI) by rosiglitazone are limited. Moreover, the effects of rosiglitazone on the function and levels of HDL are unclear. In the present study, we investigated the effects of rosiglitazone on HDL function and its mechanisms of action in atherosclerotic rabbits. Our results revealed that rosiglitazone induced a significant increase in serum HDL-C levels, paraoxonase 1 (PON1) activity, [3H]cholesterol efflux rates, and the expression of ABCA1 and SR-BI in hepatocytes and peritoneal macrophages. The expression of ABCA1 was also increased in aortic lesions. Rosiglitazone markedly reduced serum myeloperoxidase (MPO) activity, aortic intima-media thickness (IMT) and the percentage of plaque area in the aorta. It can thus be concluded that in atherosclerotic rabbits, rosigitazone increases the levels of HDL-C and hinders atherosclerosis. Thus, it improves HDL quality and function, as well as the HDL-induced cholesterol efflux, exerting anti-inflammatory and antioxidant effects. PMID:25604880




High Density Lipoproteins for the Systemic Delivery of short interfering RNA  

PubMed Central

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

McMahon, Kaylin M.; Thaxton, C. Shad



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

PubMed Central

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 honey samples exhibited more or less the same highly significant antioxidant activity within the concentration of 1mg honey/1 ml in XOD system and LDL peroxidation assays. The chemical composition of these samples was investigated by GC/MS and HPLC analysis, 11 compounds being new to honey. The GC/MS revealed the presence of 90 compounds, mainly aliphatic acids (37 compounds), which represent 54.73, 8.72, 22.87 and 64.10% and phenolic acids (15 compound) 2.3, 1.02, 2.07 and 11.68% for Acacia, Coriander, Sider and Palm honeys. In HPLC analysis, 19 flavonoids were identified. Coriander and Sider honeys were characterized by the presence of large amounts of flavonoids. PMID:18955249

Abd El-Hady, Faten K.



Serum Amyloid P Component Prevents High-Density Lipoprotein-Mediated Neutralization of Lipopolysaccharide  

PubMed Central

Lipopolysaccharide (LPS) is an amphipathic macromolecule that is highly aggregated in aqueous preparations. LPS-binding protein (LBP) catalyzes the transfer of single LPS molecules, segregated from an LPS aggregate, to high-density lipoproteins (HDL), which results in the neutralization of LPS. When fluorescein isothiocyanate-labeled LPS (FITC-LPS) is used, this transfer of LPS monomers to HDL can be measured as an increase in fluorescence due to dequenching of FITC-LPS. Recently, serum amyloid P component (SAP) was shown to neutralize LPS in vitro, although only in the presence of low concentrations of LBP. In this study, we show that SAP prevented HDL-mediated dequenching of FITC-LPS, even in the presence of high concentrations of LBP. Human bactericidal/permeability-increasing protein (BPI), a very potent LPS-binding and -neutralizing protein, also prevented HDL-mediated dequenching of FITC-LPS. Furthermore, SAP inhibited HDL-mediated neutralization of both rough and smooth LPS in a chemiluminescence assay quantifying the LPS-induced priming of neutrophils in human blood. SAP bound both isolated HDL and HDL in serum. Using HDL-coated magnetic beads prebound with SAP, we demonstrated that HDL-bound SAP prevented the binding of LPS to HDL. We suggest that SAP, by preventing LPS binding to HDL, plays a regulatory role, balancing the amount of LPS that, via HDL, is directed to the adrenal glands. PMID:10948110

de Haas, Carla J. C.; Poppelier, Miriam J. J. G.; van Kessel, Kok P. M.; van Strijp, Jos A. G.



Low-density lipoprotein-mediated delivery of docosahexaenoic acid selectively kills murine liver cancer cells  

PubMed Central

Aim The natural omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), has recently been credited for possessing anticancer properties. Herein, we investigate the cytotoxic actions of DHA-loaded low-density lipoprotein (LDL) nanoparticles in normal and liver cancer cells. Materials & methods LDL-DHA nanoparticles were prepared and subjected to extensive biophysical characterization. The therapeutic utility of LDL-DHA nanoparticles was evaluated in normal and malignant murine hepatocyte cell lines, TIB-73 and TIB-75, respectively. Results & discussion The engineered LDL-DHA nanoparticles possessed enhanced physical and oxidative stabilities over native LDL and free DHA. Dose–response studies showed that therapeutic doses of LDL-DHA nanoparticles that completely killed TIB-75 were innocuous to TIB-73. The selective induction of lipid peroxidation and reactive oxygen species in the cancer cells was shown to play a central role in LDL-DHA nanoparticle-mediated cytotoxicity. Conclusion In summary, these findings indicate that LDL-DHA nanoparticles show great promise as a selective anticancer agent against hepatocellular carcinoma. PMID:24397600

Reynolds, Lacy; Mulik, Rohit S.; Wen, Xiaodong; Dilip, Archana; Corbin, Ian R.



Role of leptin on the expression of low density lipoprotein receptor  

PubMed Central

Background & objectives: Leptin resistance oriented hyperleptinaemia is a common problem in obese subjects in association with hypercholesterolaemia. The most common target for hypercholesterolaemia is impaired low density lipoprotein receptor (LDLR). This study was carried out to investigate whether any alteration in LDLR expression could explain the occurrence of hypercholesterolaemia in the event of hyperleptinaemia. Methods: Expression of LDLR and SREBP2 (sterol regulatory element binding protein 2) were examined in HepG2 cells by RT-PCR and Western blotting. JAK2 inhibitor II was used to verify the effect of JAK-STAT (Janus Kinase-Signal Transducer and Activator of Transcription) pathway (common mediator for cytokine signaling). Co-localization of LDLR and insulin receptor (IR) was examined by confocal microscopy. Results: Leptin was found to reduce the expression of LDLR and its transcription factor SREBP2. On the other hand, a weak signal for stimulation of LDLR by leptin was noted to be mediated by JAK2 pathway. But the joint effect of the two signaling pathways kept LDLR only in depressed mode in presence of leptin. Confocal microscopy showed that LDLR made an intensively co-localized complex with insulin receptor in presence of leptin. Interpretation & conclusions: Our results show that though leptin stimulates LDLR expression very weakly through JAK-STAT signaling pathway, it mainly imposes inhibition on LDLR expression by inhibiting transcription factor SREBP2. The inter-association between LDLR and IR may be a reason to render LDLR functionally inactive in presence of leptin. PMID:25488447

Yadav, Naval Kishor; Arjuman, Albina; Chandra, Nimai C.



Uptake and Accumulation of Oxidized Low-Density Lipoprotein during Mycobacterium tuberculosis Infection in Guinea Pigs  

PubMed Central

The typical host response to infection of humans and some animals by M. tuberculosis is the accumulation of reactive oxygen species generating inflammatory cells into discrete granulomas, which frequently develop central caseous necrosis. In previous studies we showed that infection of immunologically naïve guinea pigs with M. tuberculosis leads to localized and systemic oxidative stress that results in a significant depletion of serum total antioxidant capacity and the accumulation of malondialdehyde, a bi-product of lipid peroxidation. Here we show that in addition, the generation of excessive reactive oxygen species in vivo resulted in the accumulation of oxidized low density lipoproteins (OxLDL) in pulmonary and extrapulmonary granulomas, serum and lung macrophages collected by bronchoalveolar lavage. Macrophages from immunologically naïve guinea pigs infected with M. tuberculosis also had increased surface expression of the type 1 scavenger receptors CD36 and LOX1, which facilitate the uptake of oxidized host macromolecules including OxLDL. Vaccination of guinea pigs with Bacillus Calmette Guerin (BCG) prior to aerosol challenge reduced the bacterial burden as well as the intracellular accumulation of OxLDL and the expression of macrophage CD36 and LOX1. In vitro loading of guinea pig lung macrophages with OxLDL resulted in enhanced replication of bacilli compared to macrophages loaded with non-oxidized LDL. Overall, this study provides additional evidence of oxidative stress in M. tuberculosis infected guinea pigs and the potential role OxLDL laden macrophages have in supporting intracellular bacilli survival and persistence. PMID:22493658

Palanisamy, Gopinath S.; Kirk, Natalie M.; Ackart, David F.; Obregón-Henao, Andrés; Shanley, Crystal A.; Orme, Ian M.; Basaraba, Randall J.



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



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



Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment.  


Familial hypercholesterolemia (FH) is caused predominately by variants in the low-density lipoprotein receptor gene (LDLR). We report here an update of the UCL LDLR variant database to include variants reported in the literature and in-house between 2008 and 2010, transfer of the database to LOVDv.2.0 platform ( and pathogenicity analysis. The database now contains over 1288 different variants reported in FH patients: 55% exonic substitutions, 22% exonic small rearrangements (<100 bp), 11% large rearrangements (>100 bp), 2% promoter variants, 10% intronic variants and 1 variant in the 3' untranslated sequence. The distribution and type of newly reported variants closely matches that of the 2008 database, and we have used these variants (n= 223) as a representative sample to assess the utility of standard open access software (PolyPhen, SIFT, refined SIFT, Neural Network Splice Site Prediction Tool, SplicePort and NetGene2) and additional analyses (Single Amino Acid Polymorphism database, analysis of conservation and structure and Mutation Taster) for pathogenicity prediction. In combination, these techniques have enabled us to assign with confidence pathogenic predictions to 8/8 in-frame small rearrangements and 8/9 missense substitutions with previously discordant results from PolyPhen and SIFT analysis. Overall, we conclude that 79% of the reported variants are likely to be disease causing. PMID:22881376

Usifo, Ebele; Leigh, Sarah E A; Whittall, Ros A; Lench, Nicholas; Taylor, Alison; Yeats, Corin; Orengo, Christine A; Martin, Andrew C R; Celli, Jacopo; Humphries, Steve E



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



The role of lectin-like oxidised low-density lipoprotein receptor-1 in vascular pathology.  


The lectin-like oxidised low-density lipoprotein receptor-1 (LOX-1) is a vascular scavenger receptor that plays a central role in the pathogenesis of atherothrombotic disease, which remains the main cause of mortality in the Western population. Recent evidence indicates that targeting LOX-1 represents a credible strategy for the management vascular disease and the current review explores the role of this molecule in the diagnosis and treatment of atherosclerosis. LOX-1-mediated pro-atherogenic effects can be inhibited by anti-LOX-1 monoclonal antibodies and procyanidins, whereas downregulation of LOX-1 expression has been achieved by antisense oligonucleotides and a specific pyrrole-imidazole polyamide. Furthermore, LOX-1 can be utilised for plaque imaging using monoclonal antibodies and even the selective delivery of anti-atherosclerotic agents employing immunoliposome techniques. Also, plasma levels of the circulating soluble form of LOX-1 levels are elevated in atherosclerosis and therefore may constitute an additional diagnostic biomarker of vascular pathology. PMID:25216847

Shaw, Daniel James; Seese, Rachel; Ponnambalam, Sreenivasan; Ajjan, Ramzi



Molecular dynamics on a model for nascent high-density lipoprotein: role of salt bridges.  

PubMed Central

The results of an all-atom molecular dynamics simulation on a discoidal complex made of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and a synthetic alpha-helical 18-mer peptide with an apolipoprotein-like charge distribution are presented. The system consists of 12 acetyl-18A-amide (Ac-18A-NH2) (. J. Biol. Chem. 260:10248-10255) molecules and 20 molecules of POPC in a bilayer, 10 in each leaflet, solvated in a sphere of water for a total of 28,522 atoms. The peptide molecules are oriented with their long axes normal to the bilayer (the "picket fence" orientation). This system is analogous to complexes formed in nascent high-density lipoprotein and to Ac-18A-NH2/phospholipid complexes observed experimentally. The simulation extended over 700 ps, with the last 493 ps used for analysis. The symmetry of this system allows for averaging over different helices to improve sampling, while maintaining explicit all-atom representation of all peptides. The complex is stable on the simulated time scale. Several possible salt bridges between and within helices were studied. A few salt bridge formations and disruptions were observed. Salt bridges provide specificity in interhelical interactions. PMID:10049304

Sheldahl, C; Harvey, S C



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



Polymorphism of the low-density lipoprotein receptor-related protein 5 gene and fracture risk  

PubMed Central

Several molecular epidemiological studies have been conducted to examine the association between low-density lipoprotein receptor-related proteins (LRP5) Ala1330Val polymorphism and fracture; however, the conclusions remained controversial. We therefore performed an extensive meta-analysis on 10 published studies with 184479 subjects. Electronic databases, including PubMed, Excerpta Medica Database (EMBASE), Cochrane, Elsevier Science Direct and China National Knowledge Infrastructure (CNKI) databases were searched. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random-effects models. LRP5 Ala1330Val polymorphism was associated with a significantly increased risk of fracture (OR = 1.10; 95% CI, 1.06-1.14; I2 = 29%). We also found that this polymorphism increased fracture risk in Caucasians. In the subgroup analysis according to gender, women was significantly associated with risk of fracture. In the subgroup analysis by type of fracture, LRP5 Ala1330Val polymorphism showed increased osteoporotic fracture risk. In conclusion, this meta-analysis suggested that an increased risk of fracture was associated with the LRP5 Ala1330Val polymorphism. PMID:25664010

Wang, Chao; Zhang, Gang; Gu, Mingyong; Zhou, Zhenyu; Cao, Xuecheng



Effect of Albizia julibrissin water extracts on low-density lipoprotein oxidization.  


High-value phytochemicals could be extracted from biomass prior to the current cellulosic pretreatment technologies (i.e., lime, ammonia, dilute acid, or pressurized hot water treatments) provided that the extraction is performed with a solvent that is compatible with the pretreatment. This work reports on the extraction of flavonoids from Albizia julibrissin biomass. While extracting A. julibrissin foliage with 50 degrees C water, 2.227 mg/g of hyperoside and 8.134 mg/g quercitrin were obtained, which is in the realm of what was obtained with 60% methanol. A. julibrissin foliage, flower, and whole plant extracts were tested in terms of their potential to inhibit low-density lipoprotein (LDL) oxidization. The highest inhibition was obtained with foliage water extracts, which were standardized at 2.5 microM of flavonoids. Also, the 2.5 microM foliage water extract resulted in a reduction from 43% to only 1% of the observed monocyte adherence. To have commercial application, A. julibrissin water extracts should be devoid of toxicity. The A. julibrissin foliage, flower, and whole plant water extracts were not toxic to Vero 76 cells. In summary, A. julibrissin biomass can be extracted with 50 degrees C water to yield an antioxidant stream, showing that it may be possible to couple extraction of valuable phytochemicals to the cellulosic pretreatment step. PMID:17497875

Vaughn, Katherine; McClain, Colt; Carrier, Danielle Julie; Wallace, Sunny; King, Jerry; Nagarajan, Shanmugam; Clausen, Edgar



Equilibrium and kinetic studies of the interactions of a porphyrin with low-density lipoproteins.  

PubMed Central

Low-density lipoproteins (LDL) play a key role in the delivery of photosensitizers to tumor cells in photodynamic therapy. The interaction of deuteroporphyrin, an amphiphilic porphyrin, with LDL is examined at equilibrium and the kinetics of association/dissociation are determined by stopped-flow. Changes in apoprotein and porphyrin fluorescence suggest two classes of bound porphyrins. The first class, characterized by tryptophan fluorescence quenching, involves four well-defined sites. The affinity constant per site is 8.75 x 10(7) M(-1) (cumulative affinity 3.5 x 10(8) M(-1)). The second class corresponds to the incorporation of up to 50 molecules into the outer lipidic layer of LDL with an affinity constant of 2 x 10(8) M(-1). Stopped-flow experiments involving direct LDL porphyrin mixing or porphyrin transfer from preloaded LDL to albumin provide kinetic characterization of the two classes. The rate constants for dissociation of the first and second classes are 5.8 and 15 s(-1); the association rate constants are 5 x 10(8) M(-1) s(-1) per site and 3 x 10(9) M(-1) s(-1), respectively. Both fluorescence and kinetic analysis indicate that the first class involves regions at the boundary between lipids and the apoprotein. The kinetics of porphyrin-LDL interactions indicates that changes in the distribution of photosensitizers among various carriers could be very sensitive to the specific tumor microenvironment. PMID:12496113

Bonneau, Stéphanie; Vever-Bizet, Christine; Morlière, Patrice; Mazière, Jean-Claude; Brault, Daniel



Tumor-targeted delivery of Paclitaxel using low density lipoprotein-mimetic solid lipid nanoparticles.  


Water-insoluble anticancer drugs, including paclitaxel, present severe clinical side effects when administered to patients, primarily associated with the toxicity of reagents used to solubilize the drugs. In efforts to develop alternative formulations of water-insoluble anticancer drugs suitable for intravenous administration, we developed biocompatible anticancer therapeutic solid lipid nanoparticles (SLNs), mimicking the structure and composition of natural particles, low-density lipoproteins (LDLs), for tumor-targeted delivery of paclitaxel. These therapeutic nanoparticles contained water-insoluble paclitaxel in the core with tumor-targeting ligand covalently conjugated on the polyethylene glycol (PEG)-modified surface (targeted PtSLNs). In preclinical human cancer xenograft mouse model studies, the paclitaxel-containing tumor-targeting SLNs exhibited pronounced in vivo stability and enhanced biocompatibility. Furthermore, these SLNs had superior antitumor activity to in-class nanoparticular therapeutics in clinical use (Taxol and Genexol-PM) and yielded long-term complete responses. The in vivo targeted antitumor activities of the SLN formulations in a mouse tumor model suggest that LDL-mimetic SLN formulations can be utilized as a biocompatible, tumor-targeting platform for the delivery of various anticancer therapeutics. PMID:25686010

Kim, Jin-Ho; Kim, Youngwook; Bae, Ki Hyun; Park, Tae Gwan; Lee, Jung Hee; Park, Keunchil



High-density-lipoprotein subfraction 3 interaction with glycosylphosphatidylinositol-anchored proteins.  

PubMed Central

To elucidate further the binding of high-density-lipoprotein subfraction 3 (HDL3) to cells, the involvement of glycosylphosphatidylinositol-anchored proteins (GPI-proteins) was studied. Treatment of cultured cells, such as fibroblasts or SK-MES-1 cells, with a phosphatidylinositol-specific phospholipase C (PI-PLC) significantly decreases specific HDL3 binding. Moreover, PI-PLC treatment of cultured cells or cellular plasma membrane fractions results in releasing proteins. These proteins have a soluble form and can also bind HDL3, as revealed by ligand blotting experiments with HDL3. In order to obtain enriched GPI-proteins, we used a detergent-free purification method to prepare a caveolar membrane fraction. In the caveolar fraction, we obtained, by ligand blotting experiments, the enrichment of two HDL3-binding proteins with molecular masses of 120 and 80 kDa. These proteins were also revealed in a plasma membrane preparation with two other proteins, with molecular masses of 150 and 104 kDa, and were sensitive to PI-PLC treatment. Electron microscopy also showed the binding of Au-labelled HDL3 inside the caveolar membrane invaginations. In SK-MES-1 cells, HDL3 are internalized into a particular structure, resulting in the accumulation and concentration of such specific membrane domains. To sum up, a demonstration has been made of the implication of GPI-proteins as well as caveolae in the binding of HDL3 to cells. PMID:9371696

Nion, S; Briand, O; Lestavel, S; Torpier, G; Nazih, F; Delbart, C; Fruchart, J C; Clavey, V



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



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. PMID:25197325

Gursky, Olga



Purification and Characterization of a Bovine Acetyl Low Density Lipoprotein Receptor  

NASA Astrophysics Data System (ADS)

The acetyl low density lipoprotein (LDL) receptor is expressed on macrophages and some endothelial cells and mediates macrophage--foam cell formation in culture. A 220-kDa acetyl LDL binding protein was partially purified from bovine liver membranes and was used to make a specific monoclonal antibody. The 220-kDa protein immunoprecipitated by this antibody retained binding activity, and the antibody was used to detect this protein in cells lining bovine liver sinusoids and on the surface of cultured bovine alveolar macrophages. In the human monocytic cell line THP-1, the expression of both acetyl LDL receptor activity and a 220-kDa acetyl LDL binding protein were dramatically induced in parallel after differentiation to a macrophage-like state induced by phorbol ester. The ligand specificity, tissue and cell-type specificity, and coinduction data indicated that this 220-kDa cell-surface binding protein is probably a receptor that mediates acetyl LDL endocytosis. The 220-kDa protein, which was purified 238,000-fold from bovine lung membranes to near homogeneity using monoclonal antibody affinity chromatography, is a trimer of 77-kDa subunits that contain asparagine-linked carbohydrate chains.

Kodama, Tatsuhiko; Reddy, Pranhitha; Kishimoto, Chiharu; Krieger, Monty



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.



Functional characterization and classification of frequent low-density lipoprotein receptor variants.  


Familial hypercholesterolemia (FH) is an autosomal-dominant disorder mostly caused by mutations in the low-density lipoprotein receptor (LDLR) gene leading to increased risk for premature cardiovascular diseases. According to functional studies, LDLR mutations may be classified into five classes. The main objective of this study was to characterize seven LDLR variants previously detected in FH patients. Analysis by flow cytometry and confocal microscopy of LDLR activity demonstrate that all the studied variants are pathogenic. Among the mutations located in ?-propeller, p.Trp577Gly and p.Ile624del were classified as class 2, whereas p.Arg416Trp and p.Thr454Asn as class 5. p.Phe800Glyfs*129 (located in the cytoplasmic domain), p.Cys155Tyr (located in the binding domain), and p.Asn825Lys (inside FxNPxY motif) were classified as class 2, 3, and 4, respectively. The results also show that LDLR activity of these class 4 and 5 variants is not completely abolished, showing a milder phenotype. We have also determined that statin response is more efficient lowering total cholesterol in heterozygous patients carrying p.Ile624del (class 2) compared with p.Arg416Trp and p.Thr454Asn (class 5) variants. In conclusion, these findings emphasize the importance of characterizing LDLR pathogenic variants to provide an indisputable FH diagnosis and to gain insight into the statin response depending on the LDLR class mutation. PMID:25378237

Etxebarria, Aitor; Benito-Vicente, Asier; Palacios, Lourdes; Stef, Marianne; Cenarro, Ana; Civeira, Fernando; Ostolaza, Helena; Martin, Cesar



Dietary effects on oxidation of low-density lipoprotein and atherogenesis.  


Oxidization of low-density lipoprotein (LDL) particles leads to formation of atherosclerotic lesions and increased risk of cardiovascular disease (CVD) via a complex cascade of biochemical events occurring mostly within the arterial wall. Multiple dietary factors impact LDL oxidation levels, such as fat-rich meals, hyper- and hypocaloric diets, and specific nutrients (vitamins E, C, and beta-carotene; mono- and polyunsaturated fatty acids; and polyphenolic compounds). These basic nutrients are naturally present at high concentrations, individually or in combinations, in common foods (fruits/vegetables, vegetable oils, red wine, soy, fish, tea); in turn, these foods are the main components of well-defined diets (Mediterranean, East Asian, balanced vegetarian) that display protective action against LDL oxidation and potentially against CVD. For most nutrients, however, both positive and negative evidence exists as to the extent of their antioxidant properties and protection against risk of CVD, prompting caution in the interpretation of data reports and health claims of advertised antioxidant products. PMID:17045079

Galassetti, Pietro; Pontello, Andria



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



The low-density lipoprotein receptor-related protein 1 and amyloid-? clearance in Alzheimer's disease.  


Accumulation and aggregation of amyloid-? (A?) peptides in the brain trigger the development of progressive neurodegeneration and dementia associated with Alzheimer's disease (AD). Perturbation in A? clearance, rather than A? production, is likely the cause of sporadic, late-onset AD, which accounts for the majority of AD cases. Since cellular uptake and subsequent degradation constitute a major A? clearance pathway, the receptor-mediated endocytosis of A? has been intensely investigated. Among A? receptors, the low-density lipoprotein receptor-related protein 1 (LRP1) is one of the most studied receptors. LRP1 is a large endocytic receptor for more than 40 ligands, including apolipoprotein E, ?2-macroglobulin and A?. Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in brain A? clearance. LRP1 is highly expressed in a variety of cell types in the brain including neurons, vascular cells and glial cells, where LRP1 functions to maintain brain homeostasis and control A? metabolism. LRP1-mediated endocytosis regulates cellular A? uptake by binding to A? either directly or indirectly through its co-receptors or ligands. Furthermore, LRP1 regulates several signaling pathways, which also likely influences A? endocytic pathways. In this review, we discuss how LRP1 regulates the brain A? clearance and how this unique endocytic receptor participates in AD pathogenesis. Understanding of the mechanisms underlying LRP1-mediated A? clearance should enable the rational design of novel diagnostic and therapeutic strategies for AD. PMID:24904407

Kanekiyo, Takahisa; Bu, Guojun



The role of oxidized low-density lipoproteins in atherosclerosis: the myths and the facts.  


The oxidative modification hypothesis of atherosclerosis, which assigns to oxidized low-density lipoproteins (LDLs) a crucial role in atherosclerosis initiation and progression, is still debated. This review examines the role played by oxidized LDLs in atherogenesis taking into account data derived by studies based on molecular and clinical approaches. Experimental data carried out in cellular lines and animal models of atherosclerosis support the proatherogenic role of oxidized LDLs: (a) through chemotactic and proliferating actions on monocytes/macrophages, inciting their transformation into foam cells; (b) through stimulation of smooth muscle cells (SMCs) recruitment and proliferation in the tunica intima; (c) through eliciting endothelial cells, SMCs, and macrophages apoptosis with ensuing necrotic core development. Moreover, most of the experimental data on atherosclerosis-prone animals benefiting from antioxidant treatment points towards a link between oxidative stress and atherosclerosis. The evidence coming from cohort studies demonstrating an association between oxidized LDLs and cardiovascular events, notwithstanding some discrepancies, seems to point towards a role of oxidized LDLs in atherosclerotic plaque development and destabilization. Finally, the results of randomized clinical trials employing antioxidants completed up to date, despite demonstrating no benefits in healthy populations, suggest a benefit in high-risk patients. In conclusion, available data seem to validate the oxidative modification hypothesis of atherosclerosis, although additional proofs are still needed. PMID:24222937

Maiolino, Giuseppe; Rossitto, Giacomo; Caielli, Paola; Bisogni, Valeria; Rossi, Gian Paolo; Calò, Lorenzo A



The Role of Oxidized Low-Density Lipoproteins in Atherosclerosis: The Myths and the Facts  

PubMed Central

The oxidative modification hypothesis of atherosclerosis, which assigns to oxidized low-density lipoproteins (LDLs) a crucial role in atherosclerosis initiation and progression, is still debated. This review examines the role played by oxidized LDLs in atherogenesis taking into account data derived by studies based on molecular and clinical approaches. Experimental data carried out in cellular lines and animal models of atherosclerosis support the proatherogenic role of oxidized LDLs: (a) through chemotactic and proliferating actions on monocytes/macrophages, inciting their transformation into foam cells; (b) through stimulation of smooth muscle cells (SMCs) recruitment and proliferation in the tunica intima; (c) through eliciting endothelial cells, SMCs, and macrophages apoptosis with ensuing necrotic core development. Moreover, most of the experimental data on atherosclerosis-prone animals benefiting from antioxidant treatment points towards a link between oxidative stress and atherosclerosis. The evidence coming from cohort studies demonstrating an association between oxidized LDLs and cardiovascular events, notwithstanding some discrepancies, seems to point towards a role of oxidized LDLs in atherosclerotic plaque development and destabilization. Finally, the results of randomized clinical trials employing antioxidants completed up to date, despite demonstrating no benefits in healthy populations, suggest a benefit in high-risk patients. In conclusion, available data seem to validate the oxidative modification hypothesis of atherosclerosis, although additional proofs are still needed. PMID:24222937

Maiolino, Giuseppe; Caielli, Paola; Bisogni, Valeria; Rossi, Gian Paolo; Calò, Lorenzo A.



Very-low-density lipoprotein triglyceride kinetics in acute and chronic carbohydrate-fed rats  

SciTech Connect

Very-low-density lipoprotein (VLDL)-triglyceride (TG) kinetics were examined in rats maintained on either chow and water (control) or chow and a 10% carbohydrate drinking solution (fructose or glucose). The hexose solutions were available for an acute (16 h) or chronic (14 day) period. The acute fructose (AF), acute glucose (AG), and chronic fructose (CF) groups were hypertriglyceridemic (HTG) compared with control. Plasma TG concentration in chronic glucose (CG)-fed rats was similar to control. VLDL-TG was endogenously radiolabeled in donor rats with (2-3H)-glycerol. The fractional catabolic rate (FCR) was then determined by monitoring the clearance of plasma (3H)VLDL-TG in recipient animals. Donors and recipients were treated in an identical manner. AF and CF groups had an FCR significantly lower than rats given glucose for comparable periods. Both fructose groups and the AG group also had a lower FCR than control. In contrast, FCR in the CG group was significantly higher than controls. TG production rate (TGPR) in both AF and CF fed rats did not significantly differ from controls, suggesting that the HTG observed in these animals was solely from a catabolic defect. AG- and CG-treated glucose animals both had TGPR significantly higher than controls. Therefore, overproduction of VLDL-TG contributed to the HTG associated with this carbohydrate.

Hirano, T.; Mamo, J.; Poapst, M.; Steiner, G.



Adrenal imaging with technetium-99m-labelled low density lipoproteins  

SciTech Connect

Evaluation of adrenal cortical function by external imaging is currently accomplished by injection of radiolabelled analogs of cholesterol. Although the adrenals do utilized exogenous cholesterol for steroid hormone synthesis, the cholesterol is delivered to the glands not as free cholesterol but through the uptake of low density lipoproteins (LDL), which are subsequently degraded within the adrenal cortical cells to provide cholesterol. Thus, we sought to assess the use of /sup 99m/Tc-labelled LDL injected into rabbits to obtain external images of the adrenal glands. Adrenal images of all nine rabbits tested were obtained within 18 to 21 hours after injection of /sup 99m/Tc-LDL. Seven of the rabbits were subjected to adrenal cortical suppression with dexamethasone and then all nine rabbits were imaged a second time. In the untreated animals, visualization of the adrenal glands was accompanied by normal serum cortisol concentrations and accumulation of radiolabel in the adrenals, whereas in the dexamethasone-treated animals, lack of visualization of the adrenal glands was correlated with low serum cortisols, and greatly decreased accumulation of the radionuclide in the adrenals. These findings demonstrate for the first time that LDL, when labelled with /sup 99m/Tc, can be used to evaluate adrenal cortical function by external imaging.

Isaacsohn, J.L.; Lees, A.M.; Lees, R.S.; Strauss, H.W.; Barlai-Kovach, M.; Moore, T.J.



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. PMID:25400330

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



High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies.  


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

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



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))



In vitro studies of PBT Nonwoven Fabrics adsorbent for the removal of low density lipoprotein from hyperlipemia plasma  

NASA Astrophysics Data System (ADS)

Polyanion ligands such as acrylic acid (AA) and heparin were grafted on PBT Nonwoven Fabrics (PBTNF) to study their effect on the adsorption of low density lipoprotein (LDL). These modified PBTNFs were characterized by Horizontal Attenuated Total Reflectance Fourier Transform Infrared spectroscopy and X-ray Photoelectron spectroscopy. The blood compatibilities of the modified PBTNFs were examined using in vitro hemolysis rate (HR), platelet adhesion, total protein (TP) and activated partial thromboplastin time. The results showed that direct immobilized heparin could improve PBTNF-PAA's blood compatibility and decrease the adsorption capability of useful high density lipoprotein, but would possess so low bioactivity that could not further improve the absorption of LDL and TC. Since the PBTNF-PAA55-Heparin adsorbent had quite good adsorption selectivity for these proteins, it can be an excellent candidate for depletion of LDL with good blood compatibility.

Cao, Ye; Wang, Hong; Yang, Chao; Zhong, Rui; Lei, Yu; Sun, Kang; Liu, Jiaxin



Modified Low Density Lipoprotein and Lipoprotein-Containing Circulating Immune Complexes as Diagnostic and Prognostic Biomarkers of Atherosclerosis and Type 1 Diabetes Macrovascular Disease  

PubMed Central

In atherosclerosis; blood low-density lipoproteins (LDL) are subjected to multiple enzymatic and non-enzymatic modifications that increase their atherogenicity and induce immunogenicity. Modified LDL are capable of inducing vascular inflammation through activation of innate immunity; thus, contributing to the progression of atherogenesis. The immunogenicity of modified LDL results in induction of self-antibodies specific to a certain type of modified LDL. The antibodies react with modified LDL forming circulating immune complexes. Circulating immune complexes exhibit prominent immunomodulatory properties that influence atherosclerotic inflammation. Compared to freely circulating modified LDL; modified LDL associated with the immune complexes have a more robust atherogenic and proinflammatory potential. Various lipid components of the immune complexes may serve not only as diagnostic but also as essential predictive markers of cardiovascular events in atherosclerosis. Accumulating evidence indicates that LDL-containing immune complexes can also serve as biomarker for macrovascular disease in type 1 diabetes. PMID:25050779

Orekhov, Alexander N.; Bobryshev, Yuri V.; Sobenin, Igor A.; Melnichenko, Alexandra A.; Chistiakov, Dimitry A.



Antioxidative effects of green tea polyphenols on free radical initiated and photosensitized peroxidation of human low density lipoprotein  

Microsoft Academic Search

Antioxidative effects of the main polyphenolic components extracted from green tea leaves, i.e. (?)-epicatechin (EC), (?)-epigallocatechin (EGC), (?)-epicatechin gallate (ECG), (?)-epigallocatechin gallate (EGCG) and gallic acid (GA), against free radical initiated peroxidation of human low density lipoprotein (LDL) were studied. The peroxidation was initiated either thermally by a water-soluble initiator 2,2?-azobis(2-amidinopropane hydrochloride) (AAPH), or photochemically by a triplet sensitizer benzophenone

Zai-Qun Liu; Lan-Ping Ma; Bo Zhou; Li Yang; Zhong-Li Liu



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



Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells  

Microsoft Academic Search

After exposure to low density lipoprotein (LDL) that had been minimally modified by oxidation (MM-LDL), human endothelial cells (EC) and smooth muscle cells (SMC) cultured separately or together produced 2- to 3-fold more monocyte chemotactic activity than did control cells or cells exposed to freshly isolated LDL. This increase in monocyte chemotactic activity was paralleled by increases in mRNA levels

S. D. Cushing; J. A. Berliner; A. J. Valente; M. C. Territo; M. Navab; F. Parhami; R. Gerrity; C. J. Schwartz; A. M. Fogelman



Low density lipoprotein receptor mRNA in rat liver is affected by resistant starch of beans  

Microsoft Academic Search

The effects of resistant starches of beans on serum cholesterol and hepatic low density lipoprotein (LDL) receptor mRNA in\\u000a rats were investigated. Rats were fed a cholesterol-free diet with 150 g\\/kg corn starch (CS), 150g\\/kg adzuki (Vigna angularis) starch (AS), 150 g\\/kg kintoki (Phaseolus vulgaris, variety) starch (KS), or 150 g\\/kg tebou (P. vulgaris, variety) starch (TS) for 4 wk.

Michihiro Fukushima; Tetsu Ohashi; Michiyuki Kojima; Kiyoshi Ohba; Hideki Shimizu; Kei Sonoyama; Masuo Nakano



Cocoa Flavanol-Enriched Snack Bars Containing Phytosterols Effectively Lower Total and Low Density Lipoprotein Cholesterol Levels  

Microsoft Academic Search

Background Dietary intervention studies incorporating phytosterol-enriched margarine spreads have reported significant decreases in total and low-density lipoprotein (LDL) cholesterol in populations with both normal lipid levels and those with hypercholesterolemia. There is emerging support for more diverse and lower-fat phytos- terol-enriched matrixes. Controversy exists, however, over whether phytosterol-enriched foods affect serum fat- soluble vitamins. Objective We investigated whether a flavanol-rich




Oxidative modification of low density lipoprotein (LDL) by activated human monocytes and the cell lines U937 and HL60  

Microsoft Academic Search

Summary  Human peripheral blood monocytes, upon activation, have the capacity to oxidize low density lipoprotein (LDL) and render the\\u000a LDL toxic to cultured cells. Previous studies by our laboratory indicate that this process is mediated by free radicals in\\u000a that it can be prevented by addition of free radical scavengers and antioxidants during the incubation of monocytes with LDL.\\u000a Here we

Martha K. Cathcart; Guy M. Chisolm; Amy K. McNally; Diane W. Morel



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




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



Changes in dietary lipid saturation modify fatty acid composition and high-density-lipoprotein binding of adipocyte plasma membrane13  

Microsoft Academic Search

Binding of rat high-density lipoprotein (HDL) to adipocyte plasma membranes appears to be medi- ated by specific protein-recognition sites, but membrane lipids may also affect these interactions. To study the effect of dietary fatty acid composition on adipocyte-membrane phospholipid composition and HDL binding, male Wistar rats (250 ± 10 g) were fed diets high in polyunsaturated (20% wt:wt sunflower- seed

Eva Zsigmond; Christopher Parrish; Bessie Fong


Association of UCP2 and UCP3 gene polymorphisms with serum high-density lipoprotein cholesterol among Korean women  

Microsoft Academic Search

Decreased serum high-density lipoprotein (HDL-C) cholesterol is a major risk factor for atherosclerosis and vascular disease. In this study, we assessed the association of 10 uncoupling protein (UCP) 2 and UCP3 polymorphisms with serum HDL cholesterol levels and atherogenic indexes among 658 Korean women. Among the 10 single nucleotide polymorphisms (SNPs) in the UCP2 and UCP3 genes, 2 SNPs in

Min Ho Cha; Il Chul Kim; Kil Soo Kim; Byoung Kab Kang; Sun Mi Choi; Yoosik Yoon



Relationship of oxidized low density lipoprotein with lipid profile and oxidative stress markers in healthy young adults: a translational study  

Microsoft Academic Search

Background  Despite oxidized low density lipoprotein (ox-LDL) plays important roles in the pro-inflammatory and atherosclerotic processes,\\u000a the relationships with metabolic and oxidative stress biomarkers have been only scarcely investigated in young adult people.\\u000a Thus, the aim of this study was to assess plasma ox-LDL concentrations and the potential association with oxidative stress\\u000a markers as well as with anthropometric and metabolic features

Kiriaque BF Barbosa; Ana Carolina P Volp; Helen Hermana M Hermsdorff; Iñigo Navarro-Blasco; M Ángeles Zulet; J Alfredo Martínez; Josefina Bressan



Inhibition of Oxidation of Low-Density Lipoprotein by a Novel Antioxidant, BO653, Prepared by Theoretical Design  

Microsoft Academic Search

2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butyl-benzofuran (BO-653) is a novel antioxidant synthesized by theoretical designing based on the previous experimental findings and consideration. The antioxidant activities of BO-653 against the oxidative modification of low-density lipoprotein (LDL) induced by free radicals were studied. BO-653 was consumed faster than endogenous ?-tocopherol and inhibited the formation of lipid hydroperoxides, which was observed during the consumption of ?-tocopherol. Doxyl

Noriko Noguchi; Yuko Okimoto; Jyunichi Tsuchiya; Osamu Cynshi; Tatsuhiko Kodama; Etsuo Niki



Intracellular Transport of High-Density Lipoprotein 3 in Intestinal Epithelial Cells (Caco-2) Is Tubulin Associated  

Microsoft Academic Search

Background: A retroendocytotic pathway for high-density lipoprotein 3 (HDL3) in cultured intestinal epithelial cell lines has been described. In small intestinal crypt cells and Caco-2, HDL3 is internalized, transported to lipid droplets and, after solubilization of these lipid droplets, resecreted. In the present study we examined the mechanisms of intracellular transport of HDL3 in the Caco-2 cell line. Methods: Apolipoprotein

Gerhard Rogler; Elisabeth Aschenbrenner; Volker Gross; Eduard F. Stange; Jürgen Schölmerich



Increased hepatic secretion of very-low-density-lipoprotein apolipoprotein B100 in heterozygous familial hypercholesterolaemia: a stable isotope study  

Microsoft Academic Search

We have measured the hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 (VLDL apo B) in 6 patients with heterozygous familial hypercholesterolaemia (FH) (4 males, 2 females, age 47.0 ± 2.7 years (mean ± S.E.M.), weight 71.0 ± 5.3 kg) and 6 normocholesterolaemic subjects matched for age, weight and sex (4 males, 2 females, age 47.5 ± 3.1 years, weight 70.0 ±

Michael H. Cummings; Gerald F. Watts; Margot Umpleby; Thomas R. Hennessy; Jeremy R. Quiney; Peter H. Sönksen



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



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)



The transfer of very low density lipoprotein-associated phospholipids to activated human platelets depends upon cytosolic phospholipase A2 activity  

E-print Network

The transfer of very low density lipoprotein- associated phospholipids to activated human platelets phospholipids transfer to platelets Abbreviations : PL, phospholipid; PC, phosphatidylcholine; PE We have previously reported that VLDL could transfer phospholipids (PL) to platelets

Boyer, Edmond


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



[The effect of celiprolol hydrochloride for lipid metabolism--especially for the low density lipoprotein particle size].  


Recently, much attention has been paid to small sized low density lipoprotein (LDL) as a risk factor for ischemic heart disease. We investigated the effect of celiprolol hydrochloride (CH), which is a beta 1 selective beta-blocker with high intrinsic sympathomimetic activity (ISA), on the LDL particle size. We treated 41 hypertensive patients with CH and studied the change in LDL particle size according to the score of fast beta lipoprotein and LDL relative mobility value (LDL-Rm) measured by lipoprotein polyacrylamide gel disc electrophoresis (PAGE). We also studied changes in blood pressure, total cholesterol (TC), trygiyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and midband on PAGE. Systolic and dyastolic blood pressure and pulse significantly decreased during treatment. TC levels were significantly decreased at 8 weeks in all subjects and at 4, 8 and 12 weeks in patients with a TC value of over 220 mg/dl. TG levels were significantly decreased at 4 and 8 weeks in patients with initial levels of over 150 mg/dl, and significantly increased at 4 and 8 weeks in those with initial levels of under 150 mg/dl of TG. HDL-C levels did not significantly change during treatment. LDL-C levels were significantly decreased at 4, 8 and 12 weeks in patients with initial levels of over 150 mg/dl. Apo AI, AII, B, CII, CIII and E levels did not significantly change during treatment. Fast beta lipoprotein scores did not significantly change overall during treatment, but were significantly decreased at 4 and 8 weeks in patients initial TG levels of over 150 mg/dl and at 4 and 12 weeks in those with initial levels of over 220 mg/dl of TC. LDL-Rm scores did not significantly change during treatment. Midband scores were significantly reduced overall at 8 weeks, and after 4 and 8 weeks in patients with initial TG levels of over 150 mg/dl and at 4, 8 and 12 weeks in those with initial TC levels of over 220 mg/dl. These results indicated that CH did not change LDL particle size. It was suggested that CH might be a beneficial beta-blocker from the standpoint of prevention for atherosclerosis. PMID:11431890

Totsuka, M; Miyashita, Y; Ito, Y; Oyama, T; Hashiguti, S; Watanabe, H; Shirai, K; Ban, T; Ishihara, H; Yamamoto, K; Kawano, E; Mori, J; Kanechi, M



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



The low density lipoprotein receptor-related protein mediates the cellular degradation of tissue factor pathway inhibitor.  

PubMed Central

The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) is a cell-surface glycoprotein of 4525 amino acids that functions as a hepatic endocytosis receptor for several plasma proteins. These include alpha 2-macroglobulin-protease complexes, free plasminogen activators as well as plasminogen activators complexed with their inhibitors, and beta-migrating very low density lipoproteins complexed with either apolipoprotein E or lipoprotein lipase. In the current study we used human and rat hepatoma cell lines to demonstrate that LRP can mediate the degradation of tissue factor pathway inhibitor (TFPI), a Kunitz-type plasma serine protease inhibitor that regulates tissue factor-induced blood coagulation. The cellular degradation of 125I-labeled TFPI (125I-TFPI) was inhibited more than 80% both by antibodies directed against LRP and by the LRP-associated 39-kDa protein, a protein that inhibits the binding and/or cell-mediated degradation of all ligands by LRP. Using rat hepatoma cells, we report that at 4 degrees C, 125I-TFPI binds to approximately 2 x 10(6) sites per cell with an equilibrium dissociation constant of approximately 30 nM. 125I-TFPI binding to the cell surface is not inhibited by the 39-kDa protein. Taken together, our results suggest that TFPI binds to an as-yet-unidentified cell surface molecule. After binding, LRP mediates the cellular degradation of TFPI. Images PMID:7517557

Warshawsky, I; Broze, G J; Schwartz, A L



Effect of niacin on pre?-1 high-density lipoprotein levels in diabetes.  


Pre?-1 high-density lipoprotein (HDL) is an acceptor of peripheral free cholesterol and thus a participant in reverse cholesterol transport. Because patients with diabetes may have defects in reverse cholesterol transport, we hypothesized that (1) pre?-1 HDL might be decreased in diabetes and (2) because niacin improves reverse cholesterol transport and may stimulate pre?-1 HDL maturation, niacin would further decrease steady-state levels of pre?-1 HDL in diabetes. Absolute levels of pre?-1 HDL mass were measured using an isotopic dilution-ultrafiltration assay that measures apolipoprotein (apo) A-I after physically isolating pre?-1. Plasma apo A-I concentration and routine lipids were also evaluated in 11 diabetic patients. Diabetic subjects have a nearly 50% reduction of circulating levels of pre?-1 HDL to 36 ± 22 (1 SD) ?g/mL compared with our previously published values of 73 ± 44 ?g/mL in 136 healthy subjects. After niacin therapy, there was a further 17% reduction of pre?-1 HDL levels to 30 ± 26 ?g/mL (P < .026) compared with baseline. The percentage of pre?-1 HDL in diabetic patients, as a percentage of total apo A-I, was about half of the normal value of 6.1% ± 3.6%; after niacin in diabetic patients, the percentage further decreased from 3.3% ± 2.1% to 2.3% ± 1.9% (P < .003). Absolute levels of apo A-I were similar in diabetic patients (1.14 ± 0.29) and healthy subjects (1.24 ± 0.24), and were unchanged by niacin in diabetic patients. We conclude with the novel observations that diabetes is associated with significantly reduced levels of pre?-1 HDL and that, after niacin treatment, a further lowering of pre?-1 HDL levels occur. Several altered mechanisms of RCT in diabetes are consistent with low levels of pre?-1 HDL both before and after niacin treatment. PMID:20303127

Pan, Jianqiu; Shilian, Parastou; Ishida, Brian; Wu, Xiaoshan; Kane, John P; Malloy, Mary J; Charles, M Arthur



Nicotine-Induced Expression of Low-Density Lipoprotein Receptor in Oral Epithelial Cells  

PubMed Central

Background Nicotine use is one of the most important risk factors for the development of cardiovascular and periodontal diseases. Numerous reports have suggested the possible contribution of disturbed lipid metabolism for the development of both disease groups. Despite these observations, little is known about the relationship between tobacco smoking and the development of these diseases. Our previous microarray data revealed that nicotine induced low-density lipoprotein receptor (LDLR) expression in oral epithelial cells (OECs). The aim of the present study was to confirm nicotine-mediated LDLR induction and to elucidate the signaling mechanisms leading to the augmented expression of LDLR in OECs. Methods and Results LDLR and nicotinic acetylcholine receptor (nAChR) subunit expression was detected by real-time PCR. The production of LDLR was demonstrated by immunofluorescence staining. nAChR-mediated LDLR induction was examined by pre-incubation of the cells with its specific inhibitor, ?-bungarotoxin (?-BTX). The functional importance of transcription factor specific protein 1 (Sp1) was examined by luciferase assay, mithramycin pre-incubation or by small interfering RNA (siRNA) transfection. The specific binding of Sp1 to R3 region of LDLR 5’-untranslated region was demonstrated with electrophoretic mobility shift assay (EMSA) and streptavidin-agarose precipitation assay followed by western blotting. The results confirmed that nicotine induced LDLR expression at the transcriptional level. Nicotine was sensed by nAChR and the signal was transduced by Sp1 which bound to the R3 region of LDLR gene. Augmented production of LDLR in the gingival epithelial cells was further demonstrated by immunofluorescence staining using the gingival tissues obtained from the smoking patients. Conclusions Taken together, the results suggested that nicotine might contribute to the development of both cardiovascular and periodontal diseases by inducing the LDLR in OECs thereby disturbing lipid metabolism. PMID:24358207

Ito, Satoshi; Gojoubori, Takahiro; Tsunoda, Kou; Yamaguchi, Yoko; Asano, Masatake; Goke, Eiji; Koshi, Ryosuke; Sugano, Naoyuki; Yoshinuma, Naoto; Komiyama, Kazuo; Ito, Koichi



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

PubMed Central

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

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



Simvastatin enhances oxidized?low density lipoprotein?induced macrophage autophagy and attenuates lipid aggregation.  


Macrophage autophagy exerts a protective effect in advanced atherosclerosis. It has previously been reported that oxidized low?density lipoprotein (ox?LDL) induces autophagy in endothelial cells, and simvastatin enhances autophagy in coronary arterial myocytes. However, it is currently unknown whether ox?LDL induces autophagy in macrophages, or whether simvastatin affects macrophage autophagy in atherosclerosis. The present study demonstrated that ox?LDL induced lipid accumulation in the J774A.1 macrophage cell line, in a dose?dependent manner, as determined by oil red O staining. Ox?LDL also induced autophagy in the J774A.1 cells, by converting microtubule?associated protein 1 light chain 3 (LC3) I to LC3 II, which is a well?known autophagy marker. Notably, treatment of the cells with simvastatin elevated ox?LDL?induced macrophage autophagy, this was detected through the conversion of LC3 I to LC3 II and the increased expression of Beclin1, another autophagy marker. Furthermore, it was shown that stimulation with ox?LDL led to the redistribution of green fluorescent protein (GFP)?LC3 from diffusion distribution, to the formation of puncta in the J774A.1 cells. Simvastatin promoted the ox?LDL?induced formation of GFP?LC3 puncta, as detected by confocal laser scanning microscopy. Simvastatin was also shown to inhibit ox?LDL?induced cholesterol accumulation in the J774A.1 cells, as observed by oil red O staining and CHOD?PAP assay. These results suggest that simvastatin may enhance ox?LDL?induced macrophage autophagy and attenuate lipid aggregation. PMID:25351979

Huang, Baojun; Jin, Mengxing; Yan, Hai; Cheng, Yanwei; Huang, Dake; Ying, Songcheng; Zhang, Linjie



Pine bark extract prevents low-density lipoprotein oxidation and regulates monocytic expression of antioxidant enzymes.  


Polyphenols are widely distributed in leaves, seeds, bark, and flowers and considered to have beneficial effects on cardiovascular health. We hypothesized that the potent antioxidant properties of pine bark extract (PBE) are exerted by its ability to scavenge free radicals and induce antioxidant enzymes. Therefore, we investigated the effects of PBE on low-density lipoprotein (LDL) oxidation and the antioxidant defense system in monocytes. Oxidative susceptibility of LDL was determined by lag time assay in vitro and by using a human umbilical vein endothelial cell-mediated oxidation model. THP-1 monocytic cells were treated with PBE, and the expression of antioxidant enzymes was measured by real-time polymerase chain reaction and Western blot. Pine bark extract showed radical scavenging ability and significantly inhibited free radical-induced and endothelial cell-mediated LDL oxidation in vitro. Pine bark extract treatment resulted in increases in the expressions of antioxidant enzymes, glutathione peroxidase-1, catalase, and heme oxygenase-1 in THP-1 cells. In addition, PBE induced nuclear factor-erythroid-2-related factor 2 activation, which was accompanied by the activation of extracellular signal-regulated kinase and Akt despite a down-regulation of reactive oxygen species. After the monocyte investigations, we further examined the antioxidant effect after the intake of PBE by 10 healthy male volunteers. Pine bark extract significantly prolonged the lag time of LDL oxidation. Based on our findings, it appears that PBE enhances the antioxidant defense capacity of LDL and monocytes and may play a preventive role in atherosclerosis progression. PMID:25458248

Nakayama, Shiori; Kishimoto, Yoshimi; Saita, Emi; Sugihara, Norie; Toyozaki, Miku; Taguchi, Chie; Tani, Mariko; Kamiya, Tomoyasu; Kondo, Kazuo



Role of liver sinusoidal endothelial cells and stabilins in elimination of oxidized low-density lipoproteins  

PubMed Central

Atherogenesis is associated with elevated levels of low-density lipoprotein (LDL) and its oxidized form (oxLDL) in the blood. The liver is an important scavenger organ for circulating oxLDLs. The present study aimed to examine endocytosis of mildly oxLDL (the major circulating form of oxLDLs) in liver sinusoidal endothelial cells (LSECs) and the involvement of the scavenger receptors stabilin-1 and stabilin-2 in this process. Freshly isolated LSECs, Kupffer cells (KCs), and stabilin-1- and stabilin-2-transfected human embryonic kidney cells were incubated with fluorescently labeled or radiolabeled oxLDLs [oxidized for 3 h (oxLDL3), 6 h, or 24 h (oxLDL24)] to measure endocytosis. The intracellular localization of oxLDLs and stabilins in LSECs was examined by immunofluorescence and immunogold electron microscopy. Whereas oxLDL24 was endocytosed both by LSECs and KCs, oxLDL3 (mildly oxLDL) was taken up by LSECs only. The LSEC uptake of oxLDLs was significantly inhibited by the scavenger receptor ligand formaldehyde-treated serum albumin. Uptake of all modified LDLs was high in stabilin-1-transfected cells, whereas stabilin-2-transfected cells preferentially took up oxLDL24, suggesting that stabilin-1 is a more important receptor for mildly oxLDLs than stabilin-2. Double immunogold labeling experiments in LSECs indicated interactions of stabilin-1 and stabilin-2 with oxLDL3 on the cell surface, in coated pits, and endocytic vesicles. LSECs but not KCs endocytosed mildly oxLDL. Both stabilin-1 and stabilin-2 were involved in the LSEC endocytosis of oxLDLs, but experiments with stabilin-transfected cells pointed to stabilin-1 as the most important receptor for mildly oxLDL. PMID:21030611

Li, Ruomei; Oteiza, Ana; Sørensen, Karen Kristine; McCourt, Peter; Olsen, Randi; Svistounov, Dmitri



Differential RNA interference: replacement of endogenous with recombinant low density lipoprotein receptor-related protein (LRP).  


The interpretation of experiments involving the overexpression of a recombinant cDNA is often hampered by the interference of mRNA expression from the endogenous gene locus. Unless cell lines from naturally occurring mutations or knockout mice are available, difficult and time-consuming gene targeting techniques are required to inhibit endogenous gene expression. Using a method we refer to as "differential RNA interference" we demonstrate that RNA interference can be used to selectively suppress endogenous gene expression without affecting the expression of a co-transfected recombinant version of the same protein. Functional analyses of recombinant low density lipoprotein receptor-related protein (LRP) to study its involvement in lipid metabolism have been shown to be extremely difficult due to its large cDNA and the unavailability of suitable LRP-deficient cell lines. We constructed an expression vector containing the full-length coding sequence of human LRP fused to EGFP and a vector expressing small hairpin RNA directed against the 3'-untranslated region of the wild-type human LRP mRNA (LRP-shRNA). When overexpressed, EGFP-tagged LRP colocalizes with endogenous LRP and stimulates the uptake of LRP ligands. Overexpression of LRP-shRNA vectors significantly inhibits LRP expression, as judged by quantitative RT-PCR, Western blot and immunofluorescence analysis, and it dramatically decreases receptor-associated protein (RAP) uptake. Finally, co-transfection of EGFP-LRP and LRP-shRNA vectors demonstrates selective inhibition of endogenous LRP expression without affecting simultaneous expression of recombinant LRP protein. Thus, utilization of "differential RNA interference" provides a new experimental approach to selectively study the function of any recombinant protein in any given cell line without interference of endogenous protein expression. PMID:15202569

Laatsch, Alexander; Ragozin, Sergei; Grewal, Thomas; Beisiegel, Ulrike; Joerg, Heeren



Functionalized low-density lipoprotein nanoparticles for in vivo enhancement of atherosclerosis on magnetic resonance images.  


To allow visualization of macrophage-rich and miniature-sized atheromas by magnetic resonance (MR) imaging, we have converted low-density lipoprotein (LDL) into MR-active nanoparticles via the intercalation of a 1,4,7,10-tetraazacyclodecane-1,4,7-triacetic acid (DO3A) derivative and the subsequent coordination reaction with Gd(3+). After careful removal of nonchelated Gd(3+), an MR-active LDL (Gd(3+)-LDL) with a remarkably high payload of Gd(3+) (in excess of 200 Gd(3+) atoms per particle) and a high relaxivity (r(1) = 20.1 s(-1) mM(-1) per Gd(3+) or 4040 s(-1) mM(-1) per LDL) was obtained. Dynamic light-scattering photon correlation spectroscopy (DLS) and cryo transmission electron microscope (cryoTEM) images showed that Gd(3+)-LDL particles did not aggregate and remained of a similar size (25-30 nm) to native LDL. Intravenous injection of Gd(3+)-LDL into an atherosclerotic mouse model (ApoE(-/-)) resulted in an extremely high enhancement of the atheroma-bearing aortic walls at 48 h after injection. Free Gd(3+) dissociation from Gd(3+)-LDL was not detected over the imaging time window (96 h). Because autologous LDL can be isolated, modified, and returned to the same patient, our results suggest that MR-active LDL can potentially be used as a noninfectious and nonimmunogenic imaging probe for the enhancement of atheroplaques presumably via the uptake into macrophages inside the plaque. PMID:23075169

Lowell, Andrew N; Qiao, Hui; Liu, Ting; Ishikawa, Takashi; Zhang, Hualei; Oriana, Sean; Wang, Miao; Ricciotti, Emanuela; FitzGerald, Garret A; Zhou, Rong; Yamakoshi, Yoko



Photodynamic targeting of human retinoblastoma cells using covalent low-density lipoprotein conjugates.  

PubMed Central

Combination of photosensitizers with carrier molecules has been shown to enhance the efficiency of photodynamic therapy (PDT). Owing to an increased expression of their receptors on some malignant and proliferating cells, low-density lipoproteins (LDLs) are potential endogenous carriers. A photosensitizer, chlorin e6 (Ce6), was covalently bound to LDL via carbodiimide activation. The Ce6-LDL conjugate was evaluated on a fibroblast cell line with defined LDL receptor expression and a retinoblastoma cell line (Y79). Uptake of free Ce6 and Ce6 either covalently bound to or complexed with LDL was measured by spectrofluorimetry. Phototoxicity after irradiation at 660 nm was determined by a mitochondrial activity assay (MTT). Covalent binding to LDL significantly increased the uptake of Ce6 for both cell lines by a factor of 4-5. A Ce6: LDL binding ratio of 50:1 was optimal. A receptor-mediated uptake was demonstrated by saturability and competitive inhibition by free LDL. Binding also occurred at 2 degrees C and was attributed to non-specific associations. Irradiation with 10 J cm-2 of 660 nm light after treatment of cells with Ce6-LDL conjugate reduced the MTT activity by 80%, while free or mixed Ce6 induced a maximum of 10% reduction in the MTT activity following identical treatment conditions. These data suggest that targeting of LDL receptor-bearing cells using covalently bound carriers, such as LDL, might increase the efficiency and selectivity of PDT. Intraocular tumours such as retinoblastomas could be appropriate targets for such an approach owing to the ease of access of light sources and the need for non-invasive approaches in sensitive ocular sites. PMID:9000598

Schmidt-Erfurth, U.; Diddens, H.; Birngruber, R.; Hasan, T.



Time course-changes in phosphatidylcholine profile during oxidative modification of low-density lipoprotein  

PubMed Central

Background Oxidized phosphatidylcholines (oxPC) and lysophosphatidylcholine (lysoPC) generated during the formation of oxidized low-density lipoprotein (oxLDL) are involved in atherosclerotic lesion development. We investigated the time course-changes in phosphatidylcholine (PC) molecular species during oxidation of LDL to determine how those atherogenic PCs are produced. Methods Human and rabbit LDLs were pretreated with or without a selective platelet-activating factor acetylhydrolase (PAF-AH) inhibitor. LDL was oxidized by incubation with copper sulfate, and PC profiles were analyzed by liquid chromatography-tandem mass spectrometry. Results When human LDL was oxidized, the peak areas for polyunsaturated fatty acid (PUFA)-containing PC species dramatically decreased after a short lag period, concomitantly lysoPC species increased sharply. Although a variety of oxPC species containing oxidized fatty acyl groups or cleaved acyl chains are formed during LDL oxidation, only a few oxPC products accumulated in oxLDL: 1-palmitoyl-2-(9-oxo-nonanoyl) PC and long-chain oxPC with two double bonds. Pretreatment of LDL with the PAF-AH inhibitor greatly reduced lysoPC production while it had no effect on lipid peroxidation reactions and oxPC profiles. Rabbit LDL, which has a different composition of PC molecular species and needs a longer time to reach achieve full oxidation than human LDL, also accumulated lysoPC during oxidation. The increase in lysoPC in rabbit oxLDL was suppressed by pretreatment with the PAF-AH inhibitor. The major oxPC species formed in rabbit oxLDL were almost the same as human oxLDL. Conclusions These results suggest that lysoPC species are the major products and PAF-AH activity is crucial for lysoPC generation during oxidation of LDL. The oxPC species accumulated are limited when LDL is oxidized with copper ion in vitro. PMID:24625108



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

PubMed Central

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

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



Increased susceptibility to amyloid-?-induced neurotoxicity in mice lacking the low-density lipoprotein receptor.  


Familial hypercholesterolemia is caused by inherited genetic abnormalities that directly or indirectly affect the function of the low-density lipoprotein (LDL) receptor. This condition is characterized by defective catabolism of LDL which results in increased plasma cholesterol concentrations and premature coronary artery disease. Nevertheless, there is increasing preclinical and clinical evidence indicating that familial hypercholesterolemia subjects show a particularly high incidence of mild cognitive impairment. Moreover, the LDL receptor (LDLr) has been implicated as the main central nervous system apolipoprotein E receptor that regulates amyloid deposition in distinct mouse models of ?-amyloidosis. In this regard, herein we hypothesized that the lack of LDLr would enhance the susceptibility to amyloid-?-(A?)-induced neurotoxicity in mice. Using the acute intracerebroventricular injection of aggregated A?(1-40) peptide (400 pmol/mouse), a useful approach for the investigation of molecular mechanisms involved in A? toxicity, we observed oxidative stress, neuroinflammation, and neuronal membrane damage within the hippocampus of C57BL/6 wild-type mice, which were associated with spatial reference memory and working memory impairments. In addition, our data show that LDLr knockout (LDLr(-/-)) mice, regardless of A? treatment, displayed memory deficits and increased blood-brain barrier permeability. Nonetheless, LDLr(-/-) mice treated with A?(1-40) peptide presented increased acetylcholinesterase activity, astrogliosis, oxidative imbalance, and cell permeability within the hippocampus in comparison with A?(1-40)-treated C57BL/6 wild-type mice. Overall, the present study shows that the lack of LDLr increases the susceptibility to A?-induced neurotoxicity in mice providing new evidence about the crosslink between familial hypercholesterolemia and cognitive impairment. PMID:24577472

de Oliveira, Jade; Moreira, Eduardo Luiz Gasnhar; dos Santos, Danúbia Bonfanti; Piermartiri, Tetsadê Camboim; Dutra, Rafael Cypriano; Pinton, Simone; Tasca, Carla Inês; Farina, Marcelo; Prediger, Rui Daniel Schröder; de Bem, Andreza Fabro



Early appearance of dispersed low density lipoprotein receptors on the fibroblast surface during recycling.  


We have examined the distributions of recycling low density lipoprotein receptors (LDL-Rs) as they emerge onto and cluster on the surfaces of cultured cells. Surface LDL-Rs were labeled with colloidal gold-LDL conjugates (AuLDL) and cells viewed as whole-mounts in the transmission electron microscope. The steady-state distribution of LDL-Rs on the cell surface, labeled with AuLDL at 4 degrees C, comprised ring-shaped clusters of receptors with dispersed receptors scattered amongst them. After 12 min of incubation at 37 degrees C, virtually all AuLDL probes were internalized. Electron microscopy of thin sections revealed clustered receptors in coated pits and the progressive accumulation of AuLDL in endosomes, multivesicular bodies and lysosomes. By initially blocking all surface LDL-Rs, either with unconjugated LDL or AuLDL of one size, the clustering behavior of newly emerged receptors which recycled to the cell surface was selectively visualized with an AuLDL probe of a second size over a defined time-course. Release of the blocking ligand during the time-course was found to be negligible. Newly appearing dispersed LDL-Rs were detected as early as 2 min and these were often concentrated at the cell margins. The newly labeled and preblocked LDL-Rs did not cocluster before 6 min. By 8 to 12 min, ring-shaped clusters of newly emerged receptors had formed and these were often seen associated with pre-blocked LDL-Rs. The clustering of LDL-Rs on the cell surface was independent of the presence of ligand, AuLDL. Our results indicate that LDL-Rs recycle to the cell surface where they form a dispersed population which gives rise to the ring-shaped clusters of cell surface LDL-Rs associated with coated pits. PMID:2744006

Sanan, D A; van der Westhuyzen, D R; Gevers, W; Coetzee, G A



Production of oxidized lipids during modification of low-density lipoprotein by macrophages or copper.  

PubMed Central

The oxidation of low-density lipoprotein (LDL) is implicated in atherosclerosis. Lipids and oxidized lipids were analysed by gas chromatography and gas chromatography-mass spectrometry in human LDL incubated with mouse peritoneal macrophages (MPM) or copper (II) sulphate in Ham's F-10 medium or medium alone (control). MPM-modification and copper-catalysed oxidation of LDL resulted in the formation of oxysterols, mainly cholest-5-en-3 beta,7 beta-diol (7 beta-OH-CHOL); 7%-19% of the initial cholesterol was converted to 7 beta-OH-CHOL in 24 h. 7 beta-OH-CHOL levels in control LDL were very low. The increase in 7 beta-OH-CHOL in MPM and copper-oxidized LDL was accompanied by decreases in linoleate and arachidonate and increases in the electrophoretic mobility and degradation of LDL protein by 'target' macrophages. The concerted occurrence of these processes and their similarity in both MPM-modification and copper-catalysed oxidation of LDL were suggested by the highly significant cross-correlations. The fall in polyunsaturated fatty acid (PUFA) was accompanied by a directly proportional increase in electrophoretic mobility of the LDL. Production of 7 beta-OH-CHOL and protein degradation by macrophages showed modest elevations during the initial steep fall in PUFA, and showed their greatest increases as the levels of PUFA slowly approached zero. The levels of 7 beta-OH-CHOL and the degradation of LDL by macrophages were directly proportional. The degradation of LDL by macrophages increased rapidly as the electrophoretic mobility of LDL was slowly approaching its maximum level. PMID:7999000

Carpenter, K L; Wilkins, G M; Fussell, B; Ballantine, J A; Taylor, S E; Mitchinson, M J; Leake, D S



Autoantibodies to low-density-lipoprotein-receptor-related protein 2 (LRP2) in systemic autoimmune diseases.  


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



Antioxidant alpha-keto-carboxylate pyruvate protects low-density lipoprotein and atherogenic macrophages.  


Oxidative modification of low-density lipoprotein (oxLDL) plays a pathogenic role in atherogenesis. Classical antioxidants such as L-ascorbic acid can inhibit formation of oxLDL. Alpha-Keto-carboxylates such as pyruvate and congeners also display antioxidant properties in some cell-free and intact cell systems. We tested the hypothesis that pyruvate or alpha-keto-glutarate may function as antioxidants with respect to LDL incubated with 5 or 10 microM Cu2+ alone or in combination with THP-1-derived macrophages. alpha-Hydroxy-carboxylates (L-lactate), linear aliphatic monocarboxylates (acetate/caprylate) and L-ascorbic acid served as controls. The oxLDL formation was ascertained by electrophoretic mobility and oxLDL cytotoxicity was judged by macrophage viability and thiobarbituric acid reactive substances (TBARS) formation. Cu2+ alone was not cytotoxic but increased electrophoretic mobility of cell-free LDL, stimulating TBARS. Millimolar pyruvate, alpha-ketoglutarate, or micromolar L-ascorbic acid partially inhibited oxLDL formation, while alpha-hydroxy-carboxylate or the aliphatic mono-carboxylates had no measurable antioxidant properties in cell-free LDL. Co-culture of LDL with macrophages and Cu2+ augmented TBARS release and resulted in 95% macrophage death. Pyruvate improved macrophage viability with 5 microM Cu2+ up to 60%. L-Ascorbic acid (> or = 100 microM) protected macrophages up to 80%. When > or = 100 microM L-ascorbic acid was combined with pyruvate, oxLDL formation and macrophage death were fully prevented. Thus, alpha-keto-carboxylates, but not physiological alpha-hydroxy-carboxylates or aliphatic monocarboxylates qualify as antioxidants in LDL systems. Since alpha-keto-carboxylates enhanced the antioxidant power of L-ascorbic acid, our findings may have implications for strategies attenuating atherosclerosis. PMID:12420749

Kang, Young-Hee; Park, Sung-Hee; Lee, Yong-Jin; Kang, Jung-Sook; Kang, Il-Jun; Shin, Hyun-Kyung; Park, Jung Han Yoon; Bünger, Rolf



Low-density lipoprotein receptor-related protein-1: role in the regulation of vascular integrity.  


Low-density lipoprotein receptor-related protein-1 (LRP1) is a large endocytic and signaling receptor that is widely expressed. In the liver, LRP1 plays an important role in regulating the plasma levels of blood coagulation factor VIII (fVIII) by mediating its uptake and subsequent degradation. fVIII is a key plasma protein that is deficient in hemophilia A and circulates in complex with von Willebrand factor. Because von Willebrand factor blocks binding of fVIII to LRP1, questions remain on the molecular mechanisms by which LRP1 removes fVIII from the circulation. LRP1 also regulates cell surface levels of tissue factor, a component of the extrinsic blood coagulation pathway. This occurs when tissue factor pathway inhibitor bridges the fVII/tissue factor complex to LRP1, resulting in rapid LRP1-mediated internalization and downregulation of coagulant activity. In the vasculature LRP1 also plays protective role from the development of aneurysms. Mice in which the lrp1 gene is selectively deleted in vascular smooth muscle cells develop a phenotype similar to the progression of aneurysm formation in human patient, revealing that these mice are ideal for investigating molecular mechanisms associated with aneurysm formation. Studies suggest that LRP1 protects against elastin fiber fragmentation by reducing excess protease activity in the vessel wall. These proteases include high-temperature requirement factor A1, matrix metalloproteinase 2, matrix metalloproteinase-9, and membrane associated type 1-matrix metalloproteinase. In addition, LRP1 regulates matrix deposition, in part, by modulating levels of connective tissue growth factor. Defining pathways modulated by LRP1 that lead to aneurysm formation and defining its role in thrombosis may allow for more effective intervention in patients. PMID:24504736

Strickland, Dudley K; Au, Dianaly T; Cunfer, Patricia; Muratoglu, Selen C



Mechanism of low-density lipoprotein oxidation by hemoglobin-derived iron.  


Excellular hemoglobin is an extremely active oxidant of low-density lipoproteins (LDL), a phenomenon explained so far by different mechanisms. In this study, we analyzed the mechanism of met-hemoglobin oxidability by comparing its mode of operation with other hemoproteins, met-myoglobin and horseradish peroxidase (HRP) or with free hemin. The kinetics of met-hemoglobin activity toward LDL lipids and protein differed from that of met-myoglobin and HRP, both quantitatively and qualitatively. Those differences were further clarified by analyzing heme transfer from the above-mentioned hemoproteins to LDL. It appeared that met-hemoglobin transferred most of its hemin to LDL, and the presence of H(2)O(2) accelerated the process. In contrast, met-myoglobin partially released hemin, but only in the presence of H(2)O(2), while HRP could not transfer heme at all. The minor amount of hemin transferred from met-myoglobin to LDL sufficed to trigger ApoB oxidation, forming covalent aggregates via inter-bityrosines. This indicated that heme bound to high affinity site(s) is responsible for oxidation. LDL components providing the sites were analyzed by binding heme-CO monomers to LDL. Soret spectra revealed that the high affinity site of monomeric hemin is located on the LDL protein, ApoB. The complex heme-CO-ApoB underwent instantaneous oxidation to hemin-ApoB, and the bound hemin then slowly disintegrated in conjunction with LDL oxidation. Hemopexin prevented LDL oxidation by trapping hemoprotein transferable heme. We concluded that met-hemoglobin exerts its oxidative activity on LDL via transfer of heme, which serves as a vehicle for iron insertion into the LDL protein, leading to formation of atherogenic LDL aggregates. PMID:12795592

Grinshtein, Natalie; Bamm, Vladimir Varlen; Tsemakhovich, Vladimir Abraham; Shaklai, Nurith



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.



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.



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.



Mapping the Binding Region on the Low Density Lipoprotein Receptor for Blood Coagulation Factor VIII*  

PubMed Central

Low density lipoprotein receptor (LDLR) was shown to mediate clearance of blood coagulation factor VIII (FVIII) from the circulation. To elucidate the mechanism of interaction of LDLR and FVIII, our objective was to identify the region of the receptor necessary for binding FVIII. Using surface plasmon resonance, we found that LDLR exodomain and its cluster of complement-type repeats (CRs) bind FVIII in the same mode. This indicated that the LDLR site for FVIII is located within the LDLR cluster. Similar results were obtained for another ligand of LDLR, ?-2-macroglobulin receptor-associated protein (RAP), a common ligand of receptors from the LDLR family. We further generated a set of recombinant fragments of the LDLR cluster and assessed their structural integrity by binding to RAP and by circular dichroism. A number of fragments overlapping CR.2-5 of the cluster were positive for binding RAP and FVIII. The specificity of these interactions was tested by site-directed mutagenesis of conserved tryptophans within the LDLR fragments. For FVIII, the specificity was also tested using a single-chain variable antibody fragment directed against the FVIII light chain as a competitor. Both cases resulted in decreased binding, thus confirming its specificity. The mutagenic study also showed an importance of the conserved tryptophans in LDLR for both ligands, and the competitive binding results showed an involvement of the light chain of FVIII in its interaction with LDLR. In conclusion, the region of CR.2-5 of LDLR was defined as the binding site for FVIII and RAP. PMID:23754288

Kurasawa, James H.; Shestopal, Svetlana A.; Karnaukhova, Elena; Struble, Evi B.; Lee, Timothy K.; Sarafanov, Andrey G.



Hyaluronic acid-decorated reconstituted high density lipoprotein targeting atherosclerotic lesions.  


The primary aim of our current study was to utilize hyaluronic acid (HA) to decorate reconstituted high density lipoprotein (rHDL) loaded with lovastatin (LT), termed as HA-LT-rHDL, in order to investigate whether coating HA could efficiently evade from the undesired uptake of LT-rHDL in liver mediated by scavenger receptor class B type I (SR-BI) and then greatly accumulate LT-rHDL in atherosclerotic lesions via strong HA affinity to CD44 up-regulated at inflammatory sites such as atherosclerotic lesions, thus exerting enhanced atheroprotective efficacy. In vitro characterizations indicated the successful HA decoration onto the surface of LT-rHDL, which could be indirectly verified by the increased particle size, enhanced negative surface charge and reduced in vitro drug release rate after HA decoration. Compared with rHDL without HA, HA decoration endowed rHDL with better atherosclerotic lesions targeting efficiency and lower liver accumulation, proved by results from ex vivo imaging and tissue distribution. Furthermore, atheroprotective efficacy in model animal showed that HA-LT-rHDL had the best potent efficacy than other LT preparations, which was demonstrated by the fewest atherosclerotic lesions sizes, the most minimum mean intima-media thickness (MIT), the lowest macrophage infiltration and expression of matrix metalloproteinase-9 (MMP-9), respectively. Above results demonstrated that the newly designed HA-LT-rHDL could decrease the non-targeted uptake by liver and deliver a large amount of drug into atherosclerotic lesions so as to efficiently suppress the advancement of atherosclerosis. PMID:24947229

Liu, Lisha; He, Hongliang; Zhang, Mengyuan; Zhang, Shuangshuang; Zhang, Wenli; Liu, Jianping



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


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

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



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

Microsoft Academic Search

Purpose  This study examines methylprednisolone (MPL) effects on the dynamics of hepatic low-density lipoprotein receptor (LDLR) mRNA\\u000a and plasma lipids associated with increased risks for atherosclerosis.\\u000a \\u000a \\u000a \\u000a Materials and methods  Normal male Wistar rats were given 50 mg\\/kg MPL intramuscularly (IM) and sacrificed at various times. Measurements included\\u000a plasma MPL and CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density and hepatic LDLR mRNA,

Anasuya Hazra; Nancy A. Pyszczynski; Debra C. DuBois; Richard R. Almon; William J. Jusko



Preparative isotachophoresis of human plasma high density lipoproteins HDLz and HDL  

Microsoft Academic Search

HDL, and HDL3 subclasses of human serum HDL were isolated by preparative ultracentrifugation and further analyzed by isotachophoresis on polyacrylamide gel.The HDLz divided into six subfractions and the HDL3 into ten subfractions differing in chemical composition and in apolipoprotein content. The apoA-I\\/apoA-I1 ratios differed widely among the various subfractions. The sub- fractions with the highest apoA-I\\/apoA-I1 ratio appeared to have

G. Bittolo Bon; G. Cazzolato; P. Avogaro


The Structure of Human High Density Lipoprotein and the Levels of Apolipoprotein A-I in Plasma as Determined by Radioimmunoassay  

PubMed Central

The major apoprotein of high density lipoprotein is apolipoprotein A-I (ApoA-I). In addition to being a structural component of this class of lipoproteins, ApoA-I also has a physiologic role as an activator of lecithin-cholesterol acyl transferase, an enzyme important in the metabolism of all lipoproteins. To measure ApoA-I content in human plasma, to assess its immunologic activity in hyperlipoproteinemia, and to carry out certain structural studies of high density lipoproteins, we have developed a double antibody radioimmunoassay. ApoA-I, isolated by gel filtration, was used to produce monospecific antisera. ApoA-I was iodinated by chloramine-T and the resulting [125I]-ApoA-I was purified by gel filtration. > 85% of [125I]-ApoA-I was precipitated by antibody, and 90% of bound [125I]ApoA-I was displaced by “cold” ApoA-I. Other lipoproteins and apoproteins did not react. Plasma and high density lipoprotein from normals and subjects with hyperlipoproteinemia displaced counts in parallel with ApoA-I, suggesting that the same antigenic determinants were reacting with antibody on lipid-free and lipid-associated ApoA-I. However, less than 5% of ApoA-I of high density lipoprotein reacted in the assay. Removal of the lipid by extraction increased the reactivity of ApoA-I in high density lipoprotein 15-20-fold; thus more than 95% of the ApoA-I molecules in “intact” high density lipoprotein are unreactive with antibody. Normal and hyperlipoproteinemic plasma and high density lipoproteins isolated from the same subjects continued to display parallelism with ApoA-I standard after lipid extraction, suggesting that ApoA-I of normal and hyperliproteinemic subjects are immunologically identical. About 90% of ApoA-I was in the d 1.063-1.21 fractions of normal plasma, trace quantities were found in the lipoproteins of d < 1.063, and the rest (about 10%) was in the d > 1.21 fraction. Normal plasma levels, assessed in extracted plasmas with a precision of 8%, were 100±35 mg/dl. Levels were normal in small groups of subjects with types II and IV hyperlipoproteinemia and high in pregnancy. However, larger population studies need to be performed to determine the distribution of ApoA-I levels in the various hyperlipoproteinemias. Images PMID:4136225

Schonfeld, Gustav; Pfleger, Barbara



Supernova Classes and Subclasses  

E-print Network

The discovery of many objects with unprecedented, amazing observational characteristics caused the last decade to be the most prolific period for the supernova research. Many of these new supernovae are transitional objects between existing classes, others well enter within the defined classes, but still show unique properties. This makes the traditional classification scheme inadequate to take into account the overall SN variety and, consequently, requires the introduction of new subclasses.

M. Turatto; S. Benetti; A. Pastorello



IDOL Stimulates Clathrin-Independent Endocytosis and Multivesicular Body-Mediated Lysosomal Degradation of the Low-Density Lipoprotein Receptor  

PubMed Central

The low-density lipoprotein receptor (LDLR) is a critical determinant of plasma cholesterol levels that internalizes lipoprotein cargo via clathrin-mediated endocytosis. Here, we show that the E3 ubiquitin ligase IDOL stimulates a previously unrecognized, clathrin-independent pathway for LDLR internalization. Real-time single-particle tracking and electron microscopy reveal that IDOL is recruited to the plasma membrane by LDLR, promotes LDLR internalization in the absence of clathrin or caveolae, and facilitates LDLR degradation by shuttling it into the multivesicular body (MVB) protein-sorting pathway. The IDOL-dependent degradation pathway is distinct from that mediated by PCSK9 as only IDOL employs ESCRT (endosomal-sorting complex required for transport) complexes to recognize and traffic LDLR to lysosomes. Small interfering RNA (siRNA)-mediated knockdown of ESCRT-0 (HGS) or ESCRT-I (TSG101) components prevents IDOL-mediated LDLR degradation. We further show that USP8 acts downstream of IDOL to deubiquitinate LDLR and that USP8 is required for LDLR entry into the MVB pathway. These results provide key mechanistic insights into an evolutionarily conserved pathway for the control of lipoprotein receptor expression and cellular lipid uptake. PMID:23382078

Scotti, Elena; Calamai, Martino; Goulbourne, Chris N.; Zhang, Li; Hong, Cynthia; Lin, Ron R.; Choi, Jinkuk; Pilch, Paul F.; Fong, Loren G.; Zou, Peng; Ting, Alice Y.; Pavone, Francesco S.; Young, Stephen G.



IDOL stimulates clathrin-independent endocytosis and multivesicular body-mediated lysosomal degradation of the low-density lipoprotein receptor.  


The low-density lipoprotein receptor (LDLR) is a critical determinant of plasma cholesterol levels that internalizes lipoprotein cargo via clathrin-mediated endocytosis. Here, we show that the E3 ubiquitin ligase IDOL stimulates a previously unrecognized, clathrin-independent pathway for LDLR internalization. Real-time single-particle tracking and electron microscopy reveal that IDOL is recruited to the plasma membrane by LDLR, promotes LDLR internalization in the absence of clathrin or caveolae, and facilitates LDLR degradation by shuttling it into the multivesicular body (MVB) protein-sorting pathway. The IDOL-dependent degradation pathway is distinct from that mediated by PCSK9 as only IDOL employs ESCRT (endosomal-sorting complex required for transport) complexes to recognize and traffic LDLR to lysosomes. Small interfering RNA (siRNA)-mediated knockdown of ESCRT-0 (HGS) or ESCRT-I (TSG101) components prevents IDOL-mediated LDLR degradation. We further show that USP8 acts downstream of IDOL to deubiquitinate LDLR and that USP8 is required for LDLR entry into the MVB pathway. These results provide key mechanistic insights into an evolutionarily conserved pathway for the control of lipoprotein receptor expression and cellular lipid uptake. PMID:23382078

Scotti, Elena; Calamai, Martino; Goulbourne, Chris N; Zhang, Li; Hong, Cynthia; Lin, Ron R; Choi, Jinkuk; Pilch, Paul F; Fong, Loren G; Zou, Peng; Ting, Alice Y; Pavone, Francesco S; Young, Stephen G; Tontonoz, Peter



Low-density Lipoprotein Receptor-related Protein 1 (LRP1)-dependent Cell Signaling Promotes Axonal Regeneration*  

PubMed Central

Low-density lipoprotein receptors (LRPs) are present extensively on cells outside of the nervous system and classically exert roles in lipoprotein metabolism. It has been reported recently that LRP1 activation could phosphorylate the neurotrophin receptor TrkA in PC12 cells and increase neurite outgrowth from developing cerebellar granule cells. These intriguing findings led us to explore the hypothesis that LRP1 activation would activate canonical neurotrophic factor signaling in adult neurons and promote axonal regeneration after spinal cord injury. We now find that treatment of adult rat dorsal root ganglion neurons in vitro with LRP1 agonists (the receptor binding domain of ?-2-macroglobulin or the hemopexin domain of matrix metalloproteinase 9) induces TrkC, Akt, and ERK activation; significantly increases neurite outgrowth (p < 0.01); and overcomes myelin inhibition (p < 0.05). These effects require Src family kinase activation, a classic LRP1-mediated Trk transactivator. Moreover, intrathecal infusions of LRP1 agonists significantly enhance sensory axonal sprouting and regeneration after spinal cord injury in rats compared with control-infused animals (p < 0.05). A significant role is established for lipoprotein receptors in sprouting and regeneration after CNS injury, identifying a novel class of therapeutic targets to explore for traumatic neurological disorders. PMID:23867460

Yoon, Choya; Van Niekerk, Erna A.; Henry, Kenneth; Ishikawa, Tetsuhiro; Orita, Sumihisa; Tuszynski, Mark H.; Campana, W. Marie



Low-Density Lipoprotein Cholesterol, Apolipoprotein B, and Risk of Coronary Heart Disease: From Familial Hyperlipidemia to Genomics  

PubMed Central

Coronary heart disease (CHD) affects 17 million people in the United States and accounts for over a million hospital stays each year. Technological advances, especially in genetics and genomics, have changed our understanding of the risk factors for developing CHD. The purpose of this paper is to review low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and risk of CHD. The paper focuses on five topics: 1) a description of lipoprotein classes, normal lipoprotein metabolism, and the biological mechanism of atherosclerosis; 2) a review of selected epidemiologic and clinical trial studies examining the associations between elevated LDL-C and apo B with CHD; 3) a brief review of the familial forms of hyperlipidemia; 4) a description of variants in genes that have been associated with higher LDL-C levels in candidate gene studies and genome-wide association studies (GWAS); and 5) nursing implications, including a discussion on how genetic tests are evaluated and the current clinical utility and validity of genetic tests for CHD. PMID:22531366

Austin, Melissa A.



Low-density lipoprotein cholesterol, apolipoprotein B, and risk of coronary heart disease: from familial hyperlipidemia to genomics.  


Coronary heart disease (CHD) affects 17 million people in the United States and accounts for over a million hospital stays each year. Technological advances, especially in genetics and genomics, have changed our understanding of the risk factors for developing CHD. The purpose of this article is to review low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and risk of CHD. The article focuses on five topics: (1) a description of lipoprotein classes, normal lipoprotein metabolism, and the biological mechanism of atherosclerosis; (2) a review of selected epidemiologic and clinical trial studies examining the associations between elevated LDL-C and apo B with CHD; (3) a brief review of the familial forms of hyperlipidemia; (4) a description of variants in genes that have been associated with higher LDL-C levels in candidate gene studies and genome-wide association studies (GWAS); and (5) nursing implications, including a discussion on how genetic tests are evaluated and the current clinical utility and validity of genetic tests for CHD. PMID:22531366

Imes, Christopher C; Austin, Melissa A



Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: studies in atherosclerotic mice and in humans.  


The beneficial health effects attributed to the consumption of fruit and vegetables are related, at least in part, to their antioxidant activity. Of special interest is the inverse relationship between the intake of dietary nutrients rich in polyphenols and cardiovascular diseases. This effect is attributed to polyphenols' ability to inhibit low-density lipoprotein (LDL) oxidation, macrophage foam cell formation and atherosclerosis. Pomegranate polyphenols can protect LDL against cell-mediated oxidation via two pathways, including either direct interaction of the polyphenols with the lipoprotein and/or an indirect effect through accumulation of polyphenols in arterial macrophages. Pomegranate polyphenols were shown to reduce the capacity of macrophages to oxidatively modify LDL, due to their interaction with LDL to inhibit its oxidation by scavenging reactive oxygen species and reactive nitrogen species and also due to accumulation of polyphenols in arterial macrophages; hence, the inhibition of macrophage lipid peroxidation and the formation of lipid peroxide-rich macrophages. Furthermore, pomegranate polyphenols increase serum paraoxonase activity, resulting in the hydrolysis of lipid peroxides in oxidized lipoproteins and in atherosclerotic lesions. These antioxidative and antiatherogenic effects of pomegranate polyphenols were demonstrated in vitro, as well as in vivo in humans and in atherosclerotic apolipoprotein E deficient mice. Dietary supplementation of polyphenol-rich pomegranate juice to atherosclerotic mice significantly inhibited the development of atherosclerotic lesions and this may be attributed to the protection of LDL against oxidation. PMID:12224378

Aviram, M; Dornfeld, L; Kaplan, M; Coleman, R; Gaitini, D; Nitecki, S; Hofman, A; Rosenblat, M; Volkova, N; Presser, D; Attias, J; Hayek, T; Fuhrman, B



Increased Free Cholesterol in Plasma Low and Very Low Density Lipoproteins in Non-Insulin-Dependent Diabetes Mellitus: Its Role in the Inhibition of Cholesteryl Ester Transfer  

NASA Astrophysics Data System (ADS)

Recombination of low and very low density lipoproteins (VLDL and LDL) from normal subjects with plasma from patients with non-insulin-dependent diabetes mellitus significantly increased the reduced rate of transfer of cholesteryl ester to these lipoproteins, which is characteristic of diabetic plasma, whereas diabetic VLDL and LDL reduced cholesteryl ester transfer rates in normal plasma. VLDL and LDL from diabetic plasma had an increased ratio of free cholesterol to phospholipid compared to normal, and unlike normal VLDL and LDL spontaneously lost free cholesterol to high density lipoprotein. These data suggest that the block to cholesteryl ester transfer to these lipoproteins in non-insulin-dependent diabetes is mediated by their increased free cholesterol content and may be related to the increased risk of these patients for developing atherosclerosis.

Fielding, Christopher J.; Reaven, Gerald M.; Liu, George; Fielding, Phoebe E.



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

PubMed Central

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

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



Lipoprotein Subfractions in Metabolic Syndrome and Obesity: Clinical Significance and Therapeutic Approaches  

PubMed Central

Small, dense low density lipoprotein (sdLDL) represents an emerging cardiovascular risk factor, since these particles can be associated with cardiovascular disease (CVD) independently of established risk factors, including plasma lipids. Obese subjects frequently have atherogenic dyslipidaemia, including elevated sdLDL levels, in addition to elevated triglycerides (TG), very low density lipoprotein (VLDL) and apolipoprotein-B, as well as decreased high density lipoprotein cholesterol (HDL-C) levels. Obesity-related co-morbidities, such as metabolic syndrome (MetS) are also characterized by dyslipidaemia. Therefore, agents that favourably modulate LDL subclasses may be of clinical value in these subjects. Statins are the lipid-lowering drug of choice. Also, anti-obesity and lipid lowering drugs other than statins could be useful in these patients. However, the effects of anti-obesity drugs on CVD risk factors remain unclear. We review the clinical significance of sdLDL in being overweight and obesity, as well as the efficacy of anti-obesity drugs on LDL subfractions in these individuals; a short comment on HDL subclasses is also included. Our literature search was based on PubMed and Scopus listings. Further research is required to fully explore both the significance of sdLDL and the efficacy of anti-obesity drugs on LDL subfractions in being overweight, obesity and MetS. Improving the lipoprotein profile in these patients may represent an efficient approach for reducing cardiovascular risk. PMID:23507795

Nikolic, Dragana; Katsiki, Niki; Montalto, Giuseppe; Isenovic, Esma R.; Mikhailidis, Dimitri P.; Rizzo, Manfredi



Evaluation of serum lipid concentrations and genetic variants at high-density lipoprotein metabolism loci and TIMP3 in age-related macular degeneration  

Microsoft Academic Search

PURPOSE: To analyze the association between polymorphisms in the TIMP3 gene and genes of the high-density lipoprotein (HDL) metabolism and age-related macular degeneration (AMD), and evaluate serum lipid and lipoprotein levels in AMD patients compared with control individuals. METHODS: Single nucleotide polymorphisms in or near the TIMP3, ABCA1, FADS1-3, CETP, LIPC, and LPL genes were genotyped. Serum levels of apolipoprotein

S. Fauser; D. Smailhodzic; A. Caramoy; J. P. van de Ven; B. Kirchhof; C. B. Hoyng; B. J. Klevering; S. Liakopoulos; A. I. den Hollander



Gene Expression Analyses in Cynomolgus Monkeys Provides Mechanistic Insight into High-Density Lipoprotein-Cholesterol Reduction by Androgens in Primates  

Microsoft Academic Search

Androgens increase muscle mass, decrease fat mass, and re- duce high-density lipoprotein cholesterol (HDL), but the re- lationship between body composition, lipoprotein metabo- lism, and androgens has not been explained. Here we treated ovariectomized cynomolgus monkeys with 5-dihydrotestos- terone(DHT)orvehiclefor14dandmeasuredlipoproteinand triglycerides. Nuclear magnetic resonance analysis revealed that DHT dose-dependently reduced the cholesterol content of large HDL particles and decreased mean HDL

Pascale Nantermet; Shun-ichi Harada; Yuan Liu; Spring Cheng; Colena Johnson; Yuanjiang Yu; Donald Kimme; Daniel Holder; Paul Hodor; Robert Phillips; William J. Ray



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



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 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



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


Different responses to oxidized low-density lipoproteins in human polarized macrophages  

PubMed Central

Background Oxidized low-density lipoprotein (oxLDL) uptake by macrophages plays an important role in foam cell formation. It has been suggested the presence of heterogeneous subsets of macrophage, such as M1 and M2, in human atherosclerotic lesions. To evaluate which types of macrophages contribute to atherogenesis, we performed cDNA microarray analysis to determine oxLDL-induced transcriptional alterations of each subset of macrophages. Results Human monocyte-derived macrophages were polarized toward the M1 or M2 subset, followed by treatment with oxLDL. Then gene expression levels during oxLDL treatment in each subset of macrophages were evaluated by cDNA microarray analysis and quantitative real-time RT-PCR. In terms of high-ranking upregulated genes and functional ontologies, the alterations during oxLDL treatment in M2 macrophages were similar to those in nonpolarized macrophages (M0). Molecular network analysis showed that most of the molecules in the oxLDL-induced highest scoring molecular network of M1 macrophages were directly or indirectly related to transforming growth factor (TGF)-?1. Hierarchical cluster analysis revealed commonly upregulated genes in all subset of macrophages, some of which contained antioxidant response elements (ARE) in their promoter regions. A cluster of genes that were specifically upregulated in M1 macrophages included those encoding molecules related to nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-?B) signaling pathway. Quantitative real-time RT-PCR showed that the gene expression of interleukin (IL)-8 after oxLDL treatment in M2 macrophages was markedly lower than those in M0 and M1 cells. HMOX1 gene expression levels were almost the same in all 3 subsets of macrophages even after oxLDL treatment. Conclusions The present study demonstrated transcriptional alterations in polarized macrophages during oxLDL treatment. The data suggested that oxLDL uptake may affect TGF-?1- and NF-?B-mediated functions of M1 macrophages, but not those of M0 or M2 macrophages. It is likely that M1 macrophages characteristically respond to oxLDL. PMID:21199582



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

PubMed Central

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



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.



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



Uptake of hypertriglyceridemic very low density lipoproteins and their remnants by HepG2 cells: the role of lipoprotein lipase, hepatic triglyceride lipase, and cell surface proteoglycans.  


Hypertriglyceridemic very low density lipoproteins (HTG-VLDL, S(f) 60-400) are not taken up by HepG2 cells. However, addition of bovine milk lipoprotein lipase (LPL) at physiological concentrations markedly stimulates uptake. In the present study, we determined whether: a) LPL catalytic activity is required for uptake, b) LPL functions as a ligand, and c) cell surface hepatic triglyceride lipase (HL) and/or proteoglycans are involved. Incubation of HepG2 cells with HTG-VLDL plus LPL (8 ng/ml) increased cellular cholesteryl ester (CE) 3.5-fold and triglyceride (TG) 6-fold. Heat-inactivation of LPL abolished the effect. Addition of tetrahydrolipstatin (THL, an LPL active-site inhibitor) to HTG-VLDL + LPL, inhibited the cellular increase in both CE and TG by greater than 90%. Co-incubation of HTG-VLDL + LPL with heparin, heparinase, or heparitinase, blocked CE accumulation by 70%, 48%, and 95%, respectively, but had no effect on the increase in cellular TG. Pre-treatment of cells with 1 mM 4-methylumbelliferyl-beta-D-xyloside, (beta-xyloside) to reduce cell surface proteoglycans inhibited the increase in CE induced by HTG-VLDL + LPL by 78%. HTG-VLDL remnants, prepared in vitro and isolated free of LPL activity, stimulated HepG2 cell CE 2.8-fold in the absence of added LPL, a process inhibited with THL by 66%. Addition of LPL (8 ng/ml) to remnants did not further enhance CE accumulation. HepG2 cell HL activity, released by heparin, was inhibited 95% by THL. The amount of HL activity and immunoreactive mass, released by heparin, was reduced 50-60% in beta-xyloside-treated cells. These results indicate that physiological concentrations of LPL promote HepG2 cell uptake of HTG-VLDL primarily due to remnant formation and that LPL does not play a major role as a ligand. HL activity and cell surface proteoglycans significantly enhance the subsequent uptake of VLDL remnants. PMID:9254059

Huff, M W; Miller, D B; Wolfe, B M; Connelly, P W; Sawyez, C G



Role of non-high-density lipoprotein cholesterol in predicting cerebrovascular events in patients following myocardial infarction.  


Although there appears to be a role for statins in reducing cerebrovascular events, the exact role of different lipid fractions in the etiopathogenesis of cerebrovascular disease (CVD) is not well understood. A secondary analysis of data collected for the placebo arm (n = 2,078) of the Cholesterol and Recurrent Events (CARE) trial was performed. The CARE trial was a placebo-controlled trial aimed at testing the effect of pravastatin on patients after myocardial infarction. Patients with histories of CVD were excluded from the study. A Cox proportional-hazards model was used to evaluate the association between plausible risk factors (including lipid fractions) and risk for first incident CVD in patients after myocardial infarction. At the end of 5 years, 123 patients (6%) had incident CVD after myocardial infarction (76 with stroke and 47 with transient ischemic attack). Baseline non-high-density lipoprotein (HDL) cholesterol level emerged as the only significant lipid risk factor that predicted CVD; low-density lipoprotein cholesterol and HDL cholesterol were not significant. The adjusted hazard ratios (adjusted for age, gender, hypertension, diabetes mellitus, and smoking) for CVD were 1.28 (95% confidence interval [CI] 1.06 to 1.53) for non-HDL cholesterol, 1.14 (95% CI 0.96 to 1.37) for low-density lipoprotein cholesterol, and 0.90 (95% CI 0.75 to 1.09) for HDL cholesterol (per unit SD change of lipid fractions). This relation held true regardless of the level of triglycerides. After adjustment for age and gender, the hazard ratio for the highest natural quartile of non-HDL was 1.76 (95% CI 1.05 to 2.54), compared to 1.36 (95% CI 0.89 to 1.90) for low-density lipoprotein cholesterol. In conclusion, non-HDL cholesterol is the strongest predictor among the lipid risk factors of incident CVD in patients with established coronary heart disease. PMID:22465317

Mahajan, Nitin; Ference, Brian A; Arora, Natasha; Madhavan, Ramesh; Bhattacharya, Pratik; Sudhakar, Rajeev; Sagar, Amit; Wang, Yun; Sacks, Frank; Afonso, Luis



The T705I mutation of the low density lipoprotein receptor gene (FH Paris9) does not cause familial hypercholesterolemia  

Microsoft Academic Search

Familial hypercholesterolemia (FH) is a genetic disease caused by mutations in the low-density lipoprotein receptor gene.\\u000a Among the more than 200 mutations so far identified, the T705I substitution in exon 15, designated FH-Paris 9, has been previously\\u000a described as an FH-causing mutation. During the course of denaturing gradient gel electrophoretic screening of exon 15 we\\u000a have identified the T705I single-base

Paola Lombardi; Eric J. G. Sijbrands; Sylvia Kamerling; Jan A. Gevers Leuven; Louis M. Havekes



The assembly and secretion of apolipoprotein B-48-containing very low density lipoproteins in McA-RH7777 cells.  


We have used an extraction procedure, which released membrane-bound apoB-100, to study the assembly of apoB-48 VLDL (very low density lipoproteins). This procedure released apoB-48, but not integral membrane proteins, from microsomes of McA-RH7777 cells. Upon gradient ultracentrifugation, the extracted apoB-48 migrated in the same position as the dense apoB-48-containing lipoprotein (apoB-48 HDL (high density lipoprotein)) secreted into the medium. Labeling studies with [(3)H]glycerol demonstrated that the HDL-like particle extracted from the microsomes contains both triglycerides and phosphatidylcholine. The estimated molar ratio between triglyceride and phosphatidylcholine was 0.70 +/- 0.09, supporting the possibility that the particle has a neutral lipid core. Pulse-chase experiments indicated that microsomal apoB-48 HDL can either be secreted as apoB-48 HDL or converted to apoB-48 VLDL. These results support the two-step model of VLDL assembly. To determine the size of apoB required to assemble HDL and VLDL, we produced apoB polypeptides of various lengths and followed their ability to assemble VLDL. Small amounts of apoB-40 were associated with VLDL, but most of the nascent chains associated with VLDL ranged from apoB-48 to apoB-100. Thus, efficient VLDL assembly requires apoB chains of at least apoB-48 size. Nascent polypeptides as small as apoB-20 were associated with particles in the HDL density range. Thus, the structural requirements of apoB to form HDL-like first-step particles differ from those to form second-step VLDL. Analysis of proteins in the d < 1.006 g/ml fraction after ultracentrifugation of the luminal content of the cells identified five chaperone proteins: binding protein, protein disulfide isomerase, calcium-binding protein 2, calreticulin, and glucose regulatory protein 94. Thus, intracellular VLDL is associated with a network of chaperones involved in protein folding. Pulse-chase and subcellular fractionation studies showed that apoB-48 VLDL did not accumulate in the rough endoplasmic reticulum. This finding indicates either that the two steps of apoB lipoprotein assembly occur in different compartment or that the assembled VLDL is transferred rapidly out of the rough endoplasmic reticulum. PMID:10744742

Stillemark, P; Borén, J; Andersson, M; Larsson, T; Rustaeus, S; Karlsson, K A; Olofsson, S O



Low density lipoprotein cholesterol: An association with the severity of diabetic retinopathy  

Microsoft Academic Search

Summary  Diurnal profiles of total and lipoprotein cholesterol and triglycerides were measured in 11 insulin-dependent diabetic subjects without retinopathy, 10 with background and 10 with proliferative retinopathy. The groups were closely matched for age and duration of diabetes. Total cholesterol levels were higher in patients with proliferative (5.6±0.5 mmol\\/l) than background (5.1±0.7 mmol\\/l) or no retinopathy (4.6±0.8 mmol\\/l, trend test; p

T. L. Dornan; R. D. Carter; A. J. Bron; R. C. Turner; J. I. Mann



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.



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)



CXCL16 Is Expressed in Podocytes and Acts as a Scavenger Receptor for Oxidized Low-Density Lipoprotein  

PubMed Central

Podocytes are a crucial cell type in the kidney and play an important role in the pathology of glomerular kidney diseases like membranous nephropathy (MN). The identification of new factors involved in the progression of glomerular kidney diseases is of great importance to the development of new strategies for the treatment of renal injury. Here we demonstrate that CXCL16 and ADAM10 are constitutively expressed in human podocytes in normal renal tissue. Proinflammatory cytokines like interferon-? and tumor necrosis factor-? induced the expression of cellular CXCL16 and the release of its soluble form from human podocytes. Using different metalloproteinase inhibitors, we provide evidence that ADAM10 is involved in the interferon-?- and tumor necrosis factor-?-induced shedding of CXCL16 from human podocytes. In addition, ADAM10 knockdown by siRNA significantly increased both CXCL16 levels and, surprisingly, its ADAM17-mediated release. Notably, targeting of CXCL16 in human podocytes both decreased the chemotaxis of CXCR6-expressing T cells and strongly reduced oxidized low-density lipoprotein uptake in human podocytes. Importantly, in kidney biopsies of patients with MN, increased glomerular CXCL16 expression was accompanied by high levels of oxidized low-density lipoprotein and decreased expression of ADAM10. In addition, we found increased glomerular ADAM17 expression in patients diagnosed with MN. In summary, we presume important roles for CXCL16, ADAM10, and ADAM17 in the development of MN, suggesting these proteins as new therapeutic targets in this glomerular kidney disease. PMID:19435795

Gutwein, Paul; Abdel-Bakky, Mohamed Sadek; Schramme, Anja; Doberstein, Kai; Kämpfer-Kolb, Nicole; Amann, Kerstin; Hauser, Ingeborg A.; Obermüller, Nicholas; Bartel, Christine; Abdel-Aziz, Abdel-Aziz H.; El Sayed, El Sayed M.; Pfeilschifter, Josef



Preparation of sulfonated porous carbon nanotubes/activated carbon composite beads and their adsorption of low density lipoprotein.  


The high level of low density lipoprotein (LDL) in plasma is the main cause of atherosclerosis. Hemoperfusion is an ideal therapy to lower the level of LDL in human blood system while therapeutic effect is determined by the adsorbent. The adsorbent must have suitable pore structure and specific functional groups. Carbon nanotubes (CNTs) could be a new adsorbent material because CNTs have high specific surface area and they can be modified by a variety of functional groups. Porous carbon composite beads with the CNTs and phenolic resin mixture were synthesized by suspension polymerization, following with carbonization and steam-activation. Then the porous composite beads were sulfonated with a sulfanilic acid anhydrous by diazotization and coupling reaction. The potential application of the sulfonated porous composite beads in adsorbing low density lipoprotein (LDL) from human serum was investigated. The results showed that the sulfonic acid groups on the composite beads could lower LDL levels greatly by electrostatic interaction with electropositive LDL. The higher 20-100 nm pore volume the composite beads had, the more LDL they could adsorb. The 20-100 nm pore volume was enhanced by adding more CNTs and improving CNTs dispersion (ultrasonic crushing). The sulfonated composite beads containing 45 wt% CNTs presented the highest adsorption capacity to LDL 10.46 mg/g, showing a good prospect as LDL adsorbent in hemoperfusion. PMID:21656032

Lu, Yuemei; Gong, Qianming; Lu, Fangping; Liang, Ji; Ji, Lijun; Nie, Qingdong; Zhang, Xiumei



Policosanol has no antioxidant activity in human low-density lipoprotein but increases excretion of bile acids in hamsters.  


Policosanol is a group of long chain primary alcohols and has been shown to reduce blood cholesterol levels and to inhibit the oxidation of low-density lipoprotein (LDL). The present study examined (i) the effect of policosanol supplementation in the diet on the fecal excretion of neutral and acidic sterols in hamsters and (ii) the antioxidant activity of policosanol in human LDL. Golden Syrian hamsters were divided into four groups (n = 12/each) fed one of the four diets containing 0 (control), 0.38, 0.75, and 1.50 g kg(-1) policosanol for 6 weeks. It was found that hamsters given 0.38-1.5 g kg(-1) diets had a serum total cholesterol level lowered by 15-25% and had a high-density lipoprotein cholesterol elevated by 7-16.8%. It was found that policosanol increased the excretion of acidic sterols by 25-73%. Contrary to that in previous reports, policosanol had no apparent anti-LDL oxidation activity when 1-tetracosanol, 1-hexacosanol, and 1-octacosanol were incubated in human LDL. Policosanol also possessed no scavenging activity on the free radical2,2-diphenyl-1-picrylhydrazyl. These data provide evidence that in addition to the effect of HMG-CoA reductase, the cholesterol-lowering activity of policosanol is partially mediated by its inhibition on the absorption of bile acids, but these data disprove the claim that policosanol is an antioxidant. PMID:16076108

Ng, Chi Ho; Leung, Ka Yiu; Huang, Yu; Chen, Zhen Yu



Morphological evidence that high density lipoproteins are not internalized by steroid-producing cells during in situ organ perfusion.  

PubMed Central

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 125I-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. Images PMID:6480831

Reaven, E; Chen, Y D; Spicher, M; Azhar, S



Genome-wide haplotypic testing in a Finnish cohort identifies a novel association with low-density lipoprotein cholesterol.  


We performed genome-wide tests for association between haplotype clusters and each of 9 metabolic traits in a cohort of 5402 Northern Finnish individuals genotyped for 330?000 single-nucleotide polymorphisms. The metabolic traits were body mass index, C-reactive protein, diastolic blood pressure, glucose, high-density lipoprotein (HDL), insulin, low-density lipoprotein (LDL), systolic blood pressure, and triglycerides. Haplotype clusters were determined using Beagle. There were LDL-associated clusters in the chromosome 4q13.3-q21.1 region containing the albumin (ALB) and platelet factor 4 (PF4) genes. This region has not been associated with LDL in previous genome-wide association studies. The most significant haplotype cluster in this region was associated with 0.488?mmol/l higher LDL (95% CI: 0.361-0.615?mmol/l, P-value: 6.4 × 10(-14)). We also observed three previously reported associations: Chromosome 16q13 with HDL, chromosome 1p32.3-p32.2 with LDL and chromosome 19q13.31-q13.32 with LDL. The chromosome 1 and chromosome 4 LDL associations do not reach genome-wide significance in single-marker analyses of these data, illustrating the power of haplotypic association testing. PMID:24896150

Zhang, Qian S; Browning, Brian L; Browning, Sharon R



The surface distribution of low density lipoprotein receptors on cultured fibroblasts and endothelial cells. Ultrastructural evidence for dispersed receptors.  


The distribution of low density lipoprotein (LDL) receptors marked with colloidal gold-conjugated low density lipoproteins has been mapped on the surfaces of cultured human skin fibroblasts and bovine aortic endothelial cells viewed whole in the transmission electron microscope. A dispersed or scattered population of LDL receptors, in addition to and clearly distinct from clustered receptors was detected on the surfaces of both fibroblasts and dividing endothelial cells. No LDL receptors could be detected on contact-inhibited endothelial cells. Clustered receptors imaged in whole-mount preparations were often arranged in rings with an approximate diameter of 250 nm. In ultra-thin sections of marked cells, clustered receptors were localised in coated pits while the few dispersed receptors seen were restricted to non-coated membrane regions. Clustered receptors often appeared localised on the rims of coated pits whose central areas were not marked. The dispersed population of receptors was usually distributed diffusely amongst the clusters on dividing endothelial cells and normal fibroblasts. Only the dispersed population appeared on LDL receptor internalisation-defective mutant fibroblasts. The marginal zones of both fibroblasts and dividing endothelial cells were populated by dispersed receptors. Clusters appeared further "inland" and were rarely seen near the cell margins. These results indicate that LDL receptors on dividing endothelial cells and fibroblasts may be dispersed on the cell surface upon or soon after their insertion during recycling. PMID:3583823

Sanan, D A; Van der Westhuyzen, D R; Gevers, W; Coetzee, G A



Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model.  


A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the mechanisms mediating the overproduction of very low density lipoprotein (VLDL) in the insulin resistant state. Fructose feeding for a 2-week period induced significant hypertriglyceridemia and hyperinsulinemia, and the development of whole body insulin resistance was documented using the euglycemic-hyperinsulinemic clamp technique. In vivo Triton WR-1339 studies showed evidence of VLDL-apoB overproduction in the fructose-fed hamster. Fructose feeding induced a significant increase in cellular synthesis and secretion of total triglyceride (TG) as well as VLDL-TG by primary hamster hepatocytes. Increased TG secretion was accompanied by a 4.6-fold increase in VLDL-apoB secretion. Enhanced stability of nascent apoB in fructose-fed hepatocytes was evident in intact cells as well as in a permeabilized cell system. Analysis of newly formed lipoprotein particles in hepatic microsomes revealed significant differences in the pattern and density of lipoproteins, with hepatocytes derived from fructose-fed hamsters having higher levels of luminal lipoproteins at a density of VLDL versus controls. Immunoblot analysis of the intracellular mass of microsomal triglyceride transfer protein, a key enzyme involved in VLDL assembly, showed a striking 2.1-fold elevation in hepatocytes derived from fructose-fed versus control hamsters. Direct incubation of hamster hepatocytes with various concentrations of fructose failed to show any direct stimulation of its intracellular stability or extracellular secretion, further supporting the notion that the apoB overproduction in the fructose-fed hamster may be related to the fructose-induced insulin resistance in this animal model. In summary, hepatic VLDL-apoB overproduction in fructose-fed hamsters appears to result from increased intracellular stability of nascent apoB and an enhanced expression of MTP, which act to facilitate the assembly and secretion of apoB-containing lipoprotein particles. PMID:10722675

Taghibiglou, C; Carpentier, A; Van Iderstine, S C; Chen, B; Rudy, D; Aiton, A; Lewis, G F; Adeli, K



Multi-dimensional co-separation analysis reveals protein-protein interactions defining plasma lipoprotein subspecies.  


The distribution of circulating lipoprotein particles affects the risk for cardiovascular disease (CVD) in humans. Lipoproteins are historically defined by their density, with low-density lipoproteins positively and high-density lipoproteins (HDLs) negatively associated with CVD risk in large populations. However, these broad definitions tend to obscure the remarkable heterogeneity within each class. Evidence indicates that each class is composed of physically (size, density, charge) and compositionally (protein and lipid) distinct subclasses exhibiting unique functionalities and differing effects on disease. HDLs in particular contain upward of 85 proteins of widely varying function that are differentially distributed across a broad range of particle diameters. We hypothesized that the plasma lipoproteins, particularly HDL, represent a continuum of phospholipid platforms that facilitate specific protein-protein interactions. To test this idea, we separated normal human plasma using three techniques that exploit different lipoprotein physicochemical properties (gel filtration chromatography, ionic exchange chromatography, and preparative isoelectric focusing). We then tracked the co-separation of 76 lipid-associated proteins via mass spectrometry and applied a summed correlation analysis to identify protein pairs that may co-reside on individual lipoproteins. The analysis produced 2701 pairing scores, with the top hits representing previously known protein-protein interactions as well as numerous unknown pairings. A network analysis revealed clusters of proteins with related functions, particularly lipid transport and complement regulation. The specific co-separation of protein pairs or clusters suggests the existence of stable lipoprotein subspecies that may carry out distinct functions. Further characterization of the composition and function of these subspecies may point to better targeted therapeutics aimed at CVD or other diseases. PMID:23882025

Gordon, Scott M; Deng, Jingyuan; Tomann, Alex B; Shah, Amy S; Lu, L Jason; Davidson, W Sean



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



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



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



The low density lipoprotein receptor-related protein 1: Unique tissue-specific functions revealed by selective gene knockout studies  

PubMed Central

The low-density lipoprotein (LDL) receptor-related protein (originally called LRP, but now referred to as LRP1) is a large endocytic receptor that is widely expressed in several tissues. LRP1 is a member of the LDL receptor family that plays diverse roles in various biological processes including lipoprotein metabolism, degradation of proteases, activation of lysosomal enzymes and cellular entry of bacterial toxins and viruses. Deletion of the LRP1 gene leads to lethality in mice, revealing a critical, but as of yet, undefined role in development. Tissue-specific gene deletion studies reveal an important contribution of LRP1 in the vasculature, central nervous system, in macrophages and in adipocytes. Three important properties of LRP1 dictate its diverse role in physiology: first, its ability to recognize more than thirty distinct ligands; second, its ability to bind a large number of cytoplasmic adaptor proteins via determinants located on its cytoplasmic domain in a phosphorylation-specific manner; and third, its ability to associate with and modulate the activity of other transmembrane receptors such as integrins and receptor tyrosine kinases. PMID:18626063

Lillis, Anna P.; Van Duyn, Lauren B.; Murphy-Ullrich, Joanne E.; Strickland, Dudley K.



Phospholipase D activity underlies very-low-density lipoprotein (VLDL)-induced aldosterone production in adrenal glomerulosa cells.  


Aldosterone is the mineralocorticoid responsible for sodium retention, thus increased blood volume and pressure. Excessive production of aldosterone results in high blood pressure as well as renal disease, stroke, and visual loss via both direct effects and effects on blood pressure. Weight gain is often associated with increased blood pressure, but it remains unclear how obesity increases blood pressure. Obese patients typically have higher lipoprotein levels; moreover, some studies have suggested that aldosterone levels are also elevated and represent a link between obesity and hypertension. Very-low-density lipoprotein (VLDL) functions to transport triglycerides from the liver to peripheral tissues. Although previous studies have demonstrated that VLDL can stimulate aldosterone production, the mechanisms underlying this effect are largely unclear. Here we show for the first time that phospholipase D (PLD) is involved in VLDL-induced aldosterone production in both a human adrenocortical cell line (HAC15) and primary cultures of bovine zona glomerulosa cells. Our data also reveal that PLD mediates steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2) expression via increasing the phosphorylation (activation) of their regulatory transcription factors. Finally, by using selective PLD inhibitors, our studies suggest that both PLD1 and PLD2 isoforms play an important role in VLDL-induced aldosterone production. PMID:24956203

Tsai, Ying-Ying; Rainey, William E; Pan, Zhi-qiang; Frohman, Michael A; Choudhary, Vivek; Bollag, Wendy B



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



High density lipoprotein mediates anti-inflammatory transcriptional reprogramming of macrophages via the transcriptional repressor ATF3  

PubMed Central

High Density Lipoprotein (HDL) mediates reverse cholesterol transport and it is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional repressor ATF3, as an HDL-inducible target gene in macrophages that down-regulates the expression of Toll-like receptor (TLR)-induced pro-inflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of novel HDL-based therapies. PMID:24317040

De Nardo, Dominic; Labzin, Larisa I.; Kono, Hajime; Seki, Reiko; Schmidt, Susanne V.; Beyer, Marc; Xu, Dakang; Zimmer, Sebastian; Lahrmann, Catharina; Schildberg, Frank A.; Vogelhuber, Johanna; Kraut, Michael; Ulas, Thomas; Kerksiek, Anja; Krebs, Wolfgang; Bode, Niklas; Grebe, Alena; Fitzgerald, Michael L.; Hernandez, Nicholas J.; Williams, Bryan; Knolle, Percy; Kneilling, Manfred; Röcken, Martin; Lütjohann, Dieter; Wright, Samuel D.; Schultze, Joachim L.; Latz, Eicke



Mechanobiology of low-density lipoprotein transport within an arterial wall--impact of hyperthermia and coupling effects.  


The effects of hyperthermia, coupling attributes and property variations on Low-density lipoprotein (LDL) transport within a multi-layered wall while accounting for the fluid structure interaction (FSI) is analyzed in this work. To understand the potential impact of the hyperthermia process, thermo-induced attributes are incorporated, accounting for the plasma flow, mass transfer, as well as the elastic wall structure. The coupling effect of osmotic pressure, Soret and Dufour diffusion is discussed and their influence on LDL transport is examined, demonstrating that only the Soret effect needs to be accounted for. The effect of thermal expansion on changing the behavior of flow, mass transport, and elastic structure is illustrated and analyzed while incorporating the variations in the effective LDL diffusivity and consumption rate, as well as other dominating parameters. It is shown that hyperthermia results in an enhancement in LDL transport by increasing the concentration levels within the arterial wall. PMID:24183548

Chung, Stephen; Vafai, Kambiz



The effects of perhexiline maleate on low density lipoprotein processing and cholesterol metabolism in cultured human fibroblasts.  


The effects of perhexiline maleate (PM, Pexid) on low density lipoprotein (LDL) processing and cholesterol metabolism were investigated after a 24 h pretreatment with the drug. Perhexiline maleate increased LDL uptake in the range 10(-6) to 10(-5) M (180% of control for 10(-5) M), whereas LDL binding and degradation were not affected. Sterol synthesis from sodium acetate was enhanced by perhexiline maleate (X 2.2 for 10(-5) M), while cholesterol esterification with oleic acid was decreased (40% of control for 10(-5) M). These effects of perhexiline on cholesterol metabolism are specific, since the synthesis of triacylglycerols from sodium acetate is not affected and since the incorporation of oleic acid into triacylglycerols is much less impaired. The decreased cholesterol esterification is accompanied by a reduction of acylcoenzyme A-cholesterol-O-acyltransferase (ACAT) activity measured in vitro on cell extracts. PMID:3383991

Candide, C; Mazière, J C; Mazière, C; Lageron, A; Polonovski, J



Simvastatin and Ezetimibe in Addition to Nonpharmacological Risk Factor Modification for Achieving New Low-Density Lipoprotein Cholesterol Targets  

Microsoft Academic Search

\\u000a Abstract\\u000a \\u000a \\u000a Background:\\u000a   Though guidelines emphasize low-density lipoprotein cholesterol (LDL-C) lowering as an essential strategy for cardiovascular\\u000a risk reduction, achieving target levels may be difficult.\\u000a \\u000a \\u000a \\u000a \\u000a Patients and Methods:\\u000a   The authors conducted a prospective, controlled, open-label trial examining the effectiveness and safety of high-dose fluvastatin\\u000a or a standard dosage of simvastatin plus ezetimibe, both with an intensive guideline-oriented cardiac rehabilitation program,\\u000a in

Branislav Liska; Ahmed A. Khattab; Lutz Herrmann; Mohamed Abdel-Wahab; Ronja Westphal; Ralph Tölg; Volker Geist; Gert Richardt



Properties of the Products Formed by the Activity of Serum Opacity Factor against Human Plasma High Density Lipoproteins  

PubMed Central

Serum opacity factor from Streptococcus pyogenes transfers the cholesteryl esters (CE) of ~100,000 plasma high density lipoprotein particles (HDL) to a CE-rich microemulsion (CERM) while forming neo HDL, a cholesterol-poor HDL-like particle. HDL, neo HDL, and CERM are distinct. Neo HDL is lower in free cholesterol and has lower surface and total microviscosities than HDL; the surface polarity of neo HDL and HDL are similar. CERM is much larger than HDL and richer in cholesterol and CE. Although the surface microviscosity of HDL is higher than that of CERM, they have similar total microviscosities because cholesterol partitions into the neutral lipid core. Because of its unique surface properties apo E preferentially associates with the CERM. In contrast, the composition and properties of neo HDL make it a potential acceptor of cellular cholesterol and its esterification. Thus, neo HDL and CERM are possible vehicles for improving cholesterol transport to the liver. PMID:18838065

Pownall, Henry J.; Courtney, Harry S.; Gillard, Baiba K.; Massey, John B.



Low-density lipoprotein apheresis for proteinuria in lupus nephritis with intraglomerular foam cells containing cholesterol crystals.  


A 28-year-old woman with systemic lupus erythematosus was referred to our hospital due to nephrotic-level proteinuria despite approximately 1 year of treatment with 50 to 60mg/d of prednisolone and 100 to 150mg/d of cyclosporine with methylprednisolone pulse therapy. Kidney biopsy showed diffuse global lupus nephritis (World Health Organization class 4-G A/C) with many intraglomerular foam cells containing cholesterol crystals. Surprisingly, proteinuria diminished after only 5 low-density lipoprotein (LDL) cholesterol apheresis sessions. This case demonstrated the potential of LDL apheresis to exhibit a remarkable effect on not only focal segmental glomerulosclerosis, but also other types of nephritis, particularly nephritis with intraglomerular foam cells. PMID:25542412

Shiraishi, Naoki; Kitamura, Kenichiro; Hayata, Manabu; Ogata, Tomohiro; Tajiri-Okamura, Keiko; Nakayama, Yushi; Kohda, Yukimasa; Tomita, Kimio; Mukoyama, Masashi



Bioinspired multiple-interaction model revealed in adsorption of low-density lipoprotein to surface containing saccharide and alkanesulfonate.  


A new "multiple-interaction model" for low-density lipoprotein (LDL) adsorption to a specific surface containing saccharide and alkanesulfonate ligands is proposed. The model suggests that there are interactions of the saccharide component beyond electrostatic interactions of the alkanesulfonate component that both influence the LDL adsorption process. This concept of multiple interactions between saccharide and LDL was inspired by the similarity in structures of LDL receptors (LDLR), heparin, and heparans used in LDL-apheresis. The model was confirmed by SPR analysis by the adsorption maxima on SAM surfaces with different compositions of saccharide and alkanesulfonate and additionally by CD detection of the conformation of LDL when in contact with saccharide. PMID:23742692

Li, Jing; Huang, Xiao-Jun; Vienken, Jörg; Xu, Zhi-Kang; Groth, Thomas



Extracorporeal circuit heparinization in selective low density lipoprotein apheresis: changes in patient hemostasis and low molecular weight heparin benefit.  


Treatment by low density lipoprotein (LDL) apheresis using dextran sulfate columns (DSC) leads to hemostasis alterations with prolonged activated partial thromboplastin time (APTT) of more than 120 seconds. In order to explain this hypocoagulability, we studied hemostasis parameters both in patients and in the extracorporeal circulation (ECC). Hemostasis changes are first related to unfractionated heparin (UFH)--needed to avoid circuit coagulation--which leads to high residual heparinemia in the patient (more than 3 times the recommended level for therapeutic use). Second, the hypocoagulability is induced by a coagulation factor decrease (primarily factors V, VIII, and X) mainly due to an adsorption mechanism on dextran sulfate. Studies on samples from column inflow, outflow, and eluate confirm this mechanism. Low molecular weight heparin (LMWH) can be used in LDL apheresis on DSC without major changes in lipid removal or coagulation factors compared to UFH. The benefit of using LMWH is to reduce residual heparinemia into the therapeutic range. PMID:8300550

Lorenzini, J L; Dutrillaux, F; Mousson, C; Lassale, B; Maynadié, M; Rifle, G



Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins  

PubMed Central

Hepatitis C virus (HCV) and triglyceride-rich very low-density lipoproteins (VLDLs) both are secreted uniquely by hepatocytes and circulate in blood in a complex. Here, we isolated from human hepatoma cells the membrane vesicles in which HCV replicates. These vesicles, which contain the HCV replication complex, are highly enriched in proteins required for VLDL assembly, including apolipoprotein B (apoB), apoE, and microsomal triglyceride transfer protein. In hepatoma cells that constitutively produce infectious HCV, HCV production is reduced by two agents that block VLDL assembly: an inhibitor of microsomal triglyceride transfer protein and siRNA directed against apoB. These results provide a possible explanation for the restriction of HCV production to the liver and suggest new cellular targets for treatment of HCV infection. PMID:17376867

Huang, Hua; Sun, Fang; Owen, David M.; Li, Weiping; Chen, Yan; Gale, Michael; Ye, Jin



Immunoregulation by low density lipoproteins in man. Inhibition of mitogen-induced T lymphocyte proliferation by interference with transferrin metabolism.  

PubMed Central

Human low density lipoprotein (LDL, d = 1.020-1.050 g/ml) inhibits mitogen-stimulated T lymphocyte DNA synthesis. Because both LDL and transferrin bind to specific cell surface receptors and enter cells by the similar means of receptor-mediated endocytosis, and because transferrin is necessary for lymphocyte DNA synthesis, we investigated the possibility that LDL may inhibit mitogen-stimulated lymphocyte responses by interfering with transferrin metabolism. LDL inhibited mitogen-stimulated lymphocyte [3H]thymidine incorporation in a concentration-dependent manner. The degree of inhibition was most marked in serum-free cultures, but was also observed in serum-containing cultures. The addition of transferrin not only augmented mitogen-induced lymphocyte [3H]thymidine incorporation in serum-free medium but also completely reversed the inhibitory effect of LDL in both serum-free and serum-containing media. Similar results were obtained when lymphocyte proliferation was assayed by counting the number of cells in culture. Transferrin also reversed the inhibition of lymphocyte responses caused by very low density lipoproteins and by cholesterol. The ability of transferrin to reverse the inhibitory effect of lipoproteins was specific, in that native but not denatured transferrin was effective whereas a variety of other proteins were ineffective. These results indicate that LDL inhibits mitogen-stimulated lymphocyte responses by interfering with transferrin metabolism. LDL only inhibited lymphocyte responses after a 48-h incubation if present from the initiation of the culture. By contrast, transferrin reversed inhibition when added after 24 h of the 48-h incubation. LDL did not inhibit lymphocyte responses by nonspecifically associating with transferrin. In addition, the acquisition of specific lymphocyte transferrin receptors was not blocked by LDL. Moreover, transferrin did not prevent the binding and uptake of fluorescent-labeled LDL by activated lymphocytes. Furthermore, LDL did not prevent the binding of transferrin to its receptor. Finally, LDL inhibition did not require specific high affinity cell surface receptors for cholesterol transport by LDL because similar inhibition and reversal by transferrin were observed with lymphocytes from a patient with homozygous familial hypercholesterolemia. Thus, LDL alters lymphocyte responses in a non-LDL receptor-mediated way by interfering with transferrin metabolism after specific binding of transferrin to receptors on activated lymphocytes. PMID:6323541

Cuthbert, J A; Lipsky, P E



A predictor of atheroma progression in patients achieving very low levels of low-density lipoprotein cholesterol  

PubMed Central

An aggressive reduction in low-density lipoprotein cholesterol (LDL-C) with statins produces regression or stabilization of coronary artery plaques. However, after achieving very low levels of LDL-C, atheroma regression is not observed in all patients. The purpose of the present study was to evaluate the determinants of atheroma progression despite achieving very low levels of LDL-C. The effects of 8-month statin therapy on coronary atherosclerosis were evaluated using virtual histology intravascular ultrasound in the TRUTH study. Of these, 33 patients who achieved an on-treatment LDL-C level of <70 mg/dl were divided into 2 groups according to increase in plaque volume (progressors, n= 16) or decrease in plaque volume (regressors, n= 17) during an 8-month follow-up period. At the 8-month follow-up, serum LDL-C and apolipoprotein B levels were significantly lower in progressors than in regressors; however, significant increases in high-density lipoprotein cholesterol and apolipoprotein AI and decreases in high-sensitivity C-reactive protein and oxidized LDL were observed only in regressors. The changes in the n-3 to n-6 polyunsaturated fatty acid ratios significantly differed between the 2 groups. Multivariate regression analysis showed that a decrease in the eicosapentaenoic acid + docosahexaenoic acid/arachidonic acid ratio was a significant predictor associated with atheroma progression (?= -0.512, p= 0.004). In conclusions, n-3 to n-6 polyunsaturated fatty acid ratios affected coronary artery plaque progression and regression in patients who achieved very low levels of LDL-C during statin therapy. PMID:24224137

Nozue, Tsuyoshi; Yamamoto, Shingo; Tohyama, Shinichi; Fukui, Kazuki; Umezawa, Shigeo; Onishi, Yuko; Kunishima, Tomoyuki; Hibi, Kiyoshi; Terashima, Mitsuyasu; Michishita, Ichiro



Oxidized Low-Density Lipoprotein Contributes to Atherogenesis via Co-activation of Macrophages and Mast Cells  

PubMed Central

Oxidized low-density lipoprotein (OxLDL) is a risk factor for atherosclerosis, due to its role in endothelial dysfunction and foam cell formation. Tissue-resident cells such as macrophages and mast cells release inflammatory mediators upon activation that in turn cause endothelial activation and monocyte adhesion. Two of these mediators are tumor necrosis factor (TNF)-?, produced by macrophages, and histamine, produced by mast cells. Static and microfluidic flow experiments were conducted to determine the number of adherent monocytes on vascular endothelium activated by supernatants of oxLDL-treated macrophages and mast cells or directly by oxLDL. The expression of adhesion molecules on activated endothelial cells and the concentration of TNF-? and histamine in the supernatants were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. A low dose of oxLDL (8 ?g/ml), below the threshold for the clinical presentation of coronary artery disease, was sufficient to activate both macrophages and mast cells and synergistically increase monocyte-endothelium adhesion via released TNF-? and histamine. The direct exposure of endothelial cells to a much higher dose of oxLDL (80 ?g/ml) had less effect on monocyte adhesion than the indirect activation via oxLDL-treated macrophages and mast cells. The results of this work indicate that the co-activation of macrophages and mast cells by oxLDL is an important mechanism for the endothelial dysfunction and atherogenesis. The observed synergistic effect suggests that both macrophages and mast cells play a significant role in early stages of atherosclerosis. Allergic patients with a lipid-rich diet may be at high risk for cardiovascular events due to high concentration of low-density lipoprotein and histamine in arterial vessel walls. PMID:25811595

Chen, Chong; Khismatullin, Damir B.



Circadian regulation of low density lipoprotein receptor promoter activity by CLOCK/BMAL1, Hes1 and Hes6  

PubMed Central

Low density lipoprotein receptor (LDLR) plays an important role in the cholesterol homeostasis. We examined the possible circadian regulation of LDLR and mechanism(s) underlying it. In mice, blood glucose and plasma triglyceride, total and high density lipoprotein cholesterol varied distinctively throughout a day. In addition, LDLR mRNA oscillated in the liver in a functional clock-dependent manner. Accordingly, analysis of human LDLR promoter sequence revealed three putative E-boxes, raising the possible regulation of LDLR expression by E-box-binding transcription factors. To test this possibility, human LDLR promoter reporter constructs were transfected into HepG2 cells and the effects of CLOCK/BMAL1, Hes1, and Hes6 expression were analyzed. It was found that positive circadian transcription factor complex CLOCK/BMAL1 upregulated human LDLR promoter activity in a serum-independent manner, while Hes family members Hes1 and Hes6 downregulated it only under serum-depleted conditions. Both effects were mapped to proximal promoter region of human LDLR, where mutation or deletion of well-known sterol regulatory element (SRE) abolished only the repressive effect of Hes1. Interestingly, hes6 and hes1 mRNA oscillated in an anti-phasic manner in the wild-type but not in the per1-/-per2-/- mouse. Comparative analysis of mouse, rat and human hes6 genes revealed that three E-boxes are conserved among three species. Transfection and site-directed mutagenesis studies with hes6 reporter constructs confirmed that the third E-box in the exon IV is functionally induced by CLOCK/BMAL1. Taken together, these results suggest that LDLR expression is under circadian control involving CLOCK/BMAL1 and Hes family members Hes1 and Hes6. PMID:22913986

Lee, Yeon-Ju; Han, Dong-Hee; Pak, Youngmi Kim



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



Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype.  


Proprotein convertase subtilisin kexin 9 (Pcsk9) is a subtilisin serine protease with a putative role in cholesterol metabolism. Pcsk9 expression is down-regulated by dietary cholesterol, and mutations in Pcsk9 have been associated with a form of autosomal dominant hypercholesterolemia. To study the function of Pcsk9 in mice, an adenovirus constitutively expressing murine Pcsk9 (Pcsk9-Ad) was used. Pcsk9 overexpression in wild-type mice caused a 2-fold increase in plasma total cholesterol and a 5-fold increase in non-high-density lipoprotein (HDL) cholesterol, with no increase in HDL cholesterol, as compared with mice infected with a control adenovirus. Fast protein liquid chromatography analysis showed that the increase in non-HDL cholesterol was due to an increase in low-density lipoprotein (LDL) cholesterol. This effect appeared to depend on the LDL receptor (LDLR) because LDLR knockout mice infected with Pcsk9-Ad had no change in plasma cholesterol levels as compared with knockout mice infected with a control adenovirus. Furthermore, whereas overexpression of Pcsk9 had no effect on LDLR mRNA levels, there was a near absence of LDLR protein in animals overexpressing Pcsk9. These results were confirmed in vitro by the demonstration that transfection of Pcsk9 in McA-RH7777 cells caused a reduction in LDLR protein and LDL binding. In summary, these results indicate that overexpression of Pcsk9 interferes with LDLR-mediated LDL cholesterol uptake. Because Pcsk9 and LDLR are coordinately regulated by cholesterol, Pcsk9 may be involved in a novel mechanism to modulate LDLR function by an alternative pathway than classic cholesterol inhibition of sterol regulatory element binding protein-mediated transcription. PMID:15118091

Maxwell, Kara N; Breslow, Jan L



Assignment of the Human Gene for the Low Density Lipoprotein Receptor to Chromosome 19: Synteny of a Receptor, a Ligand, and a Genetic Disease  

Microsoft Academic Search

The availability of a species-specific monoclonal antibody that recognizes the low density lipoprotein (LDL) receptor of human but not hamster origin permitted assignment of the structural gene for the human receptor to chromosome 19. The antibody was used to detect the human LDL receptor in a series of hamster-human somatic cell hybrids by two assays: (i) a structural assay that

Uta Francke; Michael S. Brown; Joseph L. Goldstein



Hepatic metabolism of colloidal gold-low-density lipoprotein complexes in the rat: evidence for bulk excretion of lysosomal contents into bile  

SciTech Connect

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 /sup 195/Au) appeared to be taken up by Kupffer cells, as were complexes of colloidal gold with albumin or polyvinylpyrrolidone. However, when these rats were also administered gadolinium chloride, which blocks Kupffer cell activity, most of the low-density lipoprotein-gold (but not gold complexed with albumin or polyvinylpyrrolidone) was taken up into hepatocytes by receptor-mediated endocytosis and concentrated in peribiliary lysosomes, as determined by electron microscopy. Colloidal gold taken up as a complex with low-density lipoprotein was excreted into the feces via the common bile duct at a maximal rate of about 5% daily, 4 to 12 days after injection. Thereafter, the rate of gold excretion fell off until reaching a plateau after 3 weeks. At this late time, most of the colloidal gold was shown by electron microscopy to be in Kupffer cells, whereas earlier (6 days after injection) it was contained mainly in older hepatocytic lysosomes, identified by lipofuscin granules. It is concluded that, in rats, hepatocytic lysosomes empty most of their contents into bile every week or two, apparently by exocytosis.

Renaud, G.; Hamilton, R.L.; Havel, R.J.



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




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

Technology Transfer Automated Retrieval System (TEKTRAN)

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


KIF6, LPA, TAS2R50, and VAMP8 genetic variation, low density lipoprotein cholesterol lowering response to pravastatin, and heart disease risk reduction in the elderly  

Technology Transfer Automated Retrieval System (TEKTRAN)

Single nucleotide polymorphisms (SNPs) at the KIF6 (kinesin like protein 6, rs20455 or 719Arg), LPA (lipoprotein(a), rs3798220), TAS2R50 (taste receptor type 2, member 50, rs1376251) and VAMP8 (vesicle-associated membrane protein 8, rs1010) have previously been associated with low density lipoprotei...


A Targeted Mutation in the Murine Gene Encoding the High Density Lipoprotein (HDL) Receptor Scavenger Receptor Class B Type I Reveals Its Key Role in HDL Metabolism  

Microsoft Academic Search

Plasma high density lipoprotein (HDL), which protects against atherosclerosis, is thought to remove cholesterol from peripheral tissues and to deliver cholesteryl esters via a selective uptake pathway to the liver (reverse cholesterol transport) and steroidogenic tissues (e.g., adrenal gland for storage and hormone synthesis). Despite its physiologic and pathophysiologic importance, the cellular metabolism of HDL has not been well defined.

Attilio Rigotti; Bernardo L. Trigatti; Marsha Penman; Helen Rayburn; Joachim Herz; Monty Krieger



Utilization of exogenous free fatty acids for the production of very low density lipoprotein triglyceride by livers of carbohydrate-fed rats  

Microsoft Academic Search

High carbohydrate diets enhance the hepatic output of very low density lipoprotein triglycerides. The fatty acids of these triglycerides could come from exogenous sources (i.e., diet or adipose tissue) or from de novo fatty acid synthesis in the liver. The role of exogenous free fatty acids was evaluated in rats fed Purina Chow or diets containing 10% fructose for up