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Sample records for increase low-density lipoprotein

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

    PubMed Central

    Choi, Sung Hee; Ginsberg, Henry N

    2011-01-01

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

  2. Moderate Exercise Increases Affinity of Large Very Low-Density Lipoproteins for Hydrolysis by Lipoprotein Lipase.

    PubMed

    Ghafouri, Khloud; Cooney, Josephine; Bedford, Dorothy K; Wilson, John; Caslake, Muriel J; Gill, Jason M R

    2015-06-01

    Postprandial triglyceride (TG) concentration is independently associated with cardiovascular disease risk. Exercise reduces postprandial TG concentrations, but the mechanisms responsible are unclear. The objective was to determine the effects of exercise on affinity of chylomicrons, large very low-density lipoproteins (VLDL1), and smaller VLDL (VLDL2) for lipoprotein lipase (LPL)-mediated TG hydrolysis. This was designed as a within-participant crossover study. The setting was a university metabolic investigation unit. Participants were 10 overweight/obese men. Participants undertook two oral fat tolerance tests, separated by 7-14 days, in which they had blood taken while fasting and for 4 hours after a high-fat mixed meal. On the afternoon before one test, they performed a 90-minute treadmill walk at 50% maximal oxygen uptake (exercise trial [EX]); no exercise was performed before the control trial (CON). We measured circulating TG-rich lipoprotein concentrations and affinity of chylomicrons, VLDL1, and VLDL2 for LPL-mediated TG hydrolysis. Exercise significantly reduced fasting VLDL1-TG concentration (CON, 0.49 [0.33-0.72] mmol.L(-1); EX, 0.36 [0.22-0.59] mmol.L(-1); geometric means [95% confidence interval]; P = .04). Time-averaged postprandial chylomicron-TG (CON, 0.55 ± 0.10 mmol.L(-1); EX, 0.39 ± 0.08 mmol.L(-1); mean ± SEM; P = .03) and VLDL1-TG (CON, 0.85 ± 0.13 mmol.L(-1); EX, 0.66 ± 0.10 mmol.L(-1); P = .01) concentrations were both lower in EX than CON. Affinity of VLDL1 for LPL-mediated TG hydrolysis increased by 2.2 (1.3-3.7)-fold [geometric mean (95% confidence interval)] (P = .02) in the fasted state and 2.6 (1.8-2.6)-fold (P = .001) postprandially. Affinity of chylomicrons and VLDL2 was not significantly different between trials. Exercise increases affinity of VLDL1 for LPL-mediated TG hydrolysis both fasting and postprandially. This mechanism is likely to contribute to the TG-lowering effect of exercise.

  3. S-adenosylmethionine increases circulating very-low density lipoprotein clearance in nonalcoholic fatty liver disease

    PubMed Central

    Martinez-Una, Maite; Varela-Rey, Marta; Mestre, Daniela; Fernandez-Ares, Larraitz; Fresnedo, Olatz; Fernandez-Ramos, David; Juan, Virginia Gutierrez-de; Martin-Guerrero, Idoia; Garcia-Orad, Africa; Luka, Zigmund; Wagner, Conrad; Lu, Shelly C; Garcia-Monzon, Carmelo; Finnell, Richard H; Aurrekoetxea, Igor; Buque, Xabier; Martinez-Chantar, M. Luz; Mato, Jose M.; Aspichueta, Patricia

    2014-01-01

    Background Very-low density-lipoproteins (VLDL) export lipids from liver to peripheral tissues and are the precursors of low-density-lipoproteins. Low levels of hepatic S-adenosylmethionine (SAMe) decrease triglyceride (TG) secretion in VLDL contributing to hepatosteatosis in methionine adenosyltransferase 1A knockout mice but nothing is known about the effect of SAMe over circulating VLDL metabolism. Objective We wanted to investigate whether excess SAMe could disrupt VLDL plasma metabolism and unravel the mechanisms involved. Methods Glycine N-methyltransferase (GNMT) knockout (KO), GNMT-PLIN2-KO and their respective wild types (WT) were used. A high fat diet (HFD) or a methionine deficient diet (MDD) was administrated to exacerbate or recover VLDL metabolism, respectively. Finally, 33 patients with nonalcoholic fatty-liver disease (NAFLD); 11 with hypertriglyceridemia and 22 with normal lipidemia were used in this study. Results We found that excess SAMe increases turnover of hepatic TG stores for secretion in VLDL in GNMT-KO mice, a model of NAFLD with high SAMe levels. The disrupted VLDL assembly resulted in the secretion of enlarged, phosphatidylethanolamine-poor, TG-and apoE-enriched VLDL-particles; special features that lead to increased VLDL clearance and decreased serum TG levels. Re-establishing normal SAMe levels restore VLDL secretion, features and metabolism. In NAFLD patients, serum TG levels are lower when hepatic GNMT-protein expression is decreased. Conclusion Excess hepatic SAMe levels disrupt VLDL assembly and features and increase circulating VLDL clearance which will cause increased VLDL-lipid supply to tissues and might contribute to the extrahepatic complications of NAFLD. Electronic word count: 235 PMID:25457203

  4. Inhibitors of cholesterol biosynthesis increase hepatic low-density lipoprotein receptor protein degradation.

    PubMed

    Ness, G C; Zhao, Z; Lopez, D

    1996-01-15

    Inhibitors of cholesterol biosynthesis are believed to lower serum cholesterol levels by enhancing the removal of serum low-density lipoprotein (LDL) by increasing hepatic LDL receptor function. Thus, the effects of several different inhibitors of cholesterol biosynthesis were examined for their effects on the expression of the hepatic LDL receptor in rats. We found that administration of inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase such as lovastatin, pravastatin, fluvastatin, and rivastatin resulted in increased hepatic LDL receptor mRNA levels. Surprisingly, these agents failed to increase levels of immunoreactive LDL receptor protein in rat liver even when the dose and length of treatment were increased. Treatment of rats with zaragozic acid A, an inhibitor of squalene synthase, caused even greater increases in hepatic LDL receptor mRNA levels, but did not increase levels of immunoreactive protein. Further investigation revealed that the rate of degradation of the hepatic LDL receptor was increased in rats given inhibitors of cholesterol biosynthesis. The greatest increase in the rate of degradation was seen in animals treated with zaragozic acid A which caused the largest increase in hepatic LDL receptor mRNA levels. In contrast, hepatic LDL receptor protein was stabilized in cholesterol-fed rats. It appears that increased potential for LDL receptor protein synthesis, reflected in increased mRNA levels, is offset by a corresponding increase in the rate of receptor protein degradation resulting in constant steady-state levels of hepatic LDL receptor protein. These findings are suggestive of increased cycling of the hepatic LDL receptor. This postulated mechanism can provide for enhanced hepatic uptake of lipoproteins without increasing steady-state levels of LDL receptor protein.

  5. Carbamylated low-density lipoprotein induces proliferation and increases adhesion molecule expression of human coronary artery smooth muscle cells.

    PubMed

    Asci, Gulay; Basci, Ali; Shah, Sudhir V; Basnakian, Alexei; Toz, Huseyin; Ozkahya, Mehmet; Duman, Soner; Ok, Ercan

    2008-12-01

    Presence of accelerated atherosclerosis in dialysis patients cannot be entirely explained by conventional risk factors. Exposure to urea, which is elevated in patients with kidney disease, leads to the carbamylation of proteins. We investigated the effects of carbamylated low-density lipoprotein (cLDL) on human coronary artery vascular smooth muscle cells (VSMC). Native LDL (nLDL) was carbamylated with potassium cyanate. Cells were incubated with different concentrations of cLDL carbamylated at different time points. Cytotoxicity, apoptosis, proliferation (bromodeoxyuridine incorporation), expression of adhesion molecules and extracellular matrix protein synthesis were studied. Carbamylated low-density lipoprotein exposure leads to morphological alterations and presence of cellular debris. Neither nLDL nor cLDL caused apoptosis. Lactate dehydrogenase (LDH) release was not different between groups. Carbamylated low-density lipoprotein led to a striking proliferation in VSMC compared to nLDL. Carbamylated low-density lipoprotein significantly increased intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression compared to the control. The effects of cLDL on proliferation and adhesion molecule expression were dose-dependent and correlated with the degree of low-density lipoprotein carbamylation. cLDL had no effect on extracellular matrix protein synthesis. The results support the hypothesis that cLDL may contribute to the pathogenesis of atherosclerosis in uraemic patients.

  6. Oxidized low density lipoprotein increases acetylcholinesterase activity correlating with reactive oxygen species production.

    PubMed

    Yamchuen, Panit; Aimjongjun, Sathid; Limpeanchob, Nanteetip

    2014-12-01

    Hyperlipidemia, low density lipoproteins (LDL) and their oxidized forms, and oxidative stress are suspected to be a key combination in the onset of AD and acetylcholinesterase (AChE) plays a part in this pathology. The present study aimed to link these parameters using differentiated SH-SY5Y human neuroblastoma cells in culture. Both mildly and fully oxidized human LDL (mox- and fox-LDL), but not native (non-oxidized) LDL were cytotoxic in dose- and time-dependent patterns and this was accompanied by an increased production of intracellular reactive oxygen species (ROS). Oxidized LDL (10-200 μg/mL) augmented AChE activity after 4 and 24h treatments, respectively while the native LDL was without effect. The increased AChE with oxidized LDLs was accompanied by a proportionate increase in intracellular ROS formation (R=0.904). These findings support the notion that oxidized LDLs are cytotoxic and that their action on AChE may reduce central cholinergic transmission in AD and affirm AChE as a continued rational for anticholinesterase therapy but in conjunction with antioxidant/antihyperlipidemic cotreatments.

  7. Plasma high density lipoprotein is increased in man when low density lipoprotein (LDL) is lowered by LDL-pheresis.

    PubMed Central

    Parker, T S; Gordon, B R; Saal, S D; Rubin, A L; Ahrens, E H

    1986-01-01

    Plasma high density lipoprotein (HDL) concentrations were increased in five hypercholesterolemic normoglyceridemic patients after removal of plasma low density lipoprotein (LDL) by LDL-pheresis. In each patient up to 80% of circulating LDL was removed by passing plasma through immunoadsorption columns containing antibody to apolipoprotein B immobilized to Sepharose. Rebound of LDL was slow after the procedure: 5-7 days in four non-familial hypercholesterolemic patients and greater than 14 days in one patient with homozygous familial hypercholesterolemia. Plasma HDL rose above the pretreatment baseline during the interval between treatments in four of the five patients. When treatments were repeated weekly, time-averaged plasma LDL was lowered by 40-70%, while plasma HDL cholesterol and apolipoprotein AI were increased up to 2-fold, depending on the degree of LDL lowering. Plasma HDL concentrations fell back to their baseline values when LDL-pheresis was stopped and rose again when treatment was restarted. Thus, LDL-pheresis may augment the therapeutic effectiveness of LDL lowering by raising plasma HDL levels and the concentration of HDL relative to LDL. PMID:3511474

  8. Cholecystectomy increases hepatic triglyceride content and very-low-density lipoproteins production in mice.

    PubMed

    Amigo, Ludwig; Husche, Constanze; Zanlungo, Silvana; Lütjohann, Dieter; Arrese, Marco; Miquel, Juan Francisco; Rigotti, Attilio; Nervi, Flavio

    2011-01-01

    Bile acid (BA) pool size remains unchanged after cholecystectomy (XGB) but it circulates faster, exposing the enterohepatic system to an increased flux of BA. Triglyceride (TG) and BA metabolisms are functionally inter-related. We investigated whether ablation of the gallbladder (GB) modifies hepatic TG metabolism. Male mice were subjected to XGB and fed a normal diet. In some experiments, mice received a 1% nicotinic acid diet to block lipolysis. Parameters of BA and TG metabolism, and microsomal triglyceride transfer protein (MTTP) activity were measured 1-2 months after XGB. Serum parameters, hepatic lipids and mRNA expression of genes of lipid metabolism were determined. BA pool size and synthesis were normal, but biliary BA secretion doubled during the diurnal light phase in XGB mice. Serum and hepatic TG concentrations increased 25% (P<0.02), and hepatic very-low-density lipoproteins (VLDL)-TG and apoB-48 productions increased 15% (P<0.03) and 50% (P<0.01), respectively, after XGB. Feeding a 1% nicotinic acid did normalize VLDL production. MTTP activity increased 15% (P<0.005) after XGB. Hepatic free fatty acid (FFA) synthesis and content, and mRNA levels of lipid metabolism-related genes remained normal in XGD mice. XGB increased serum and hepatic TG levels, and VLDL production, which were restored to normal by nicotinic acid. The results suggest that FFA flux from adipose tissue to the liver is increased in XGB mice. They support the hypothesis that the GB has a role in the regulation of hepatic TG metabolism and that XGB may favour the accumulation of fat in the liver. © 2010 John Wiley & Sons A/S.

  9. High density lipoprotein level is negatively associated with the increase of oxidized low density lipoprotein lipids after a fatty meal.

    PubMed

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

    2014-12-01

    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.

  10. Electronegative Low-density Lipoprotein Increases Coronary Artery Disease Risk in Uremia Patients on Maintenance Hemodialysis

    PubMed Central

    Chang, Chiz-Tzung; Wang, Guei-Jane; Kuo, Chin-Chi; Hsieh, Ju-Yi; Lee, An-Sean; Chang, Chia-Ming; Wang, Chun-Cheng; Shen, Ming-Yi; Huang, Chiu-Ching; Sawamura, Tatsuya; Yang, Chao-Yuh; Stancel, Nicole; Chen, Chu-Huang

    2016-01-01

    Abstract Electronegative low-density lipoprotein (LDL) is a recognized factor in the pathogenesis of coronary artery disease (CAD) in the general population, but its role in the development of CAD in uremia patients is unknown. L5 is the most electronegative subfraction of LDL isolated from human plasma. In this study, we examined the distribution of L5 (L5%) and its association with CAD risk in uremia patients. The LDL of 39 uremia patients on maintenance hemodialysis and 21 healthy controls was separated into 5 subfractions, L1–L5, with increasing electronegativity. We compared the distribution and composition of plasma L5 between uremia patients and controls, examined the association between plasma L5% and CAD risk in uremia patients, and studied the effects of L5 from uremia patients on endothelial function. Compared to controls, uremia patients had significantly increased L5% (P < 0.001) and L5 that was rich in apolipoprotein C3 and triglycerides. L5% was significantly higher in uremia patients with CAD (n = 10) than in those without CAD (n = 29) (P < 0.05). Independent of other major CAD risk factors, the adjusted odds ratio for CAD was 1.88 per percent increase in plasma L5% (95% CI, 1.01–3.53), with a near-linear dose–response relationship. Compared with controls, uremia patients had decreased flow-mediated vascular dilatation. In ex vivo studies with preconstricted rat thoracic aortic rings, L5 from uremia patients inhibited acetylcholine-induced relaxation. In cultured human endothelial cells, L5 inhibited endothelial nitric oxide synthase activation and induced endothelial dysfunction. Our findings suggest that elevated plasma L5% may induce endothelial dysfunction and play an important role in the increased risk of CAD in uremia patients. PMID:26765403

  11. 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.

    PubMed Central

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

    1998-01-01

    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

  12. Increased expression of low-density lipoprotein receptors in a Smith-Lemli-Opitz infant with elevated bilirubin levels.

    PubMed

    Ness, G C; Lopez, D; Borrego, O; Gilbert-Barness, E

    1997-01-31

    We report on an infant girl with severe RSH or Smith-Lemli-Opitz syndrome with hyperbilirubinemia. The infant died at age 2 months. Sterol analysis of liver and brain tissues showed marked elevations of 7-dehydrocholesterol with decreased levels of cholesterol. Immunocytochemical analysis demonstrated remarkable increases in low-density lipoprotein (LDL) receptors in these tissues, indicative of a deficiency in available cholesterol for tissue needs.

  13. Low-Density Lipoprotein Apheresis

    PubMed Central

    2007-01-01

    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

  14. Lecithin:cholesterol acyltransferase deficiency increases atherosclerosis in the low density lipoprotein receptor and apolipoprotein E knockout mice.

    PubMed

    Furbee, James W; Sawyer, Janet K; Parks, John S

    2002-02-01

    The purpose of the present study was to test the hypothesis that lecithin:cholesterol acyltransferase (LCAT) deficiency would accelerate atherosclerosis development in low density lipoprotein (LDL) receptor (LDLr-/-) and apoE (apoE-/-) knockout mice. After 16 weeks of atherogenic diet (0.1% cholesterol, 10% calories from palm oil) consumption, LDLr-/- LCAT-/- double knockout mice, compared with LDLr-/- mice, had similar plasma concentrations of free (FC), esterified (EC), and apoB lipoprotein cholesterol, increased plasma concentrations of phospholipid and triglyceride, decreased HDL cholesterol, and 2-fold more aortic FC (142 +/- 28 versus 61 +/- 20 mg/g protein) and EC (102 +/- 27 versus 61+/- 27 mg/g). ApoE-/- LCAT-/- mice fed the atherogenic diet, compared with apoE-/- mice, had higher concentrations of plasma FC, EC, apoB lipoprotein cholesterol, and phospholipid, and significantly more aortic FC (149 +/- 62 versus 109 +/- 33 mg/g) and EC (101 +/- 23 versus 69 +/- 20 mg/g) than did the apoE-/- mice. LCAT deficiency resulted in a 12-fold increase in the ratio of saturated + monounsaturated to polyunsaturated cholesteryl esters in apoB lipoproteins in LDLr-/- mice and a 3-fold increase in the apoE-/- mice compared with their counterparts with active LCAT. We conclude that LCAT deficiency in LDLr-/- and apoE-/- mice fed an atherogenic diet resulted in increased aortic cholesterol deposition, likely due to a reduction in plasma HDL, an increased saturation of cholesteryl esters in apoB lipoproteins and, in the apoE-/- background, an increased plasma concentration of apoB lipoproteins.

  15. Chitosan oligosaccharide decreases very-low-density lipoprotein triglyceride and increases high-density lipoprotein cholesterol in high-fat-diet-fed rats.

    PubMed

    Wang, Daxin; Han, Jiju; Yu, Yang; Li, Xueping; Wang, Yun; Tian, Hua; Guo, Shoudong; Jin, Shiguang; Luo, Tian; Qin, Shucun

    2011-09-01

    It is well known that chitosan has beneficial lipid-regulating effects, but it remains unknown whether chitosan oligosaccharide (COS), the chitosan degradation product, has the same lipid benefits. High-fat-diet-fed Wistar rats were administrated with COS by gastric gavage for three weeks. The effects of COS on lipids, lipoprotein components and lipid metabolism related protein activities were investigated. Plasma lipids level assays by an enzyme method showed that COS decreased triglyceride (TG) by 29-31%, and increased high-density lipoprotein (HDL) cholesterol by 8-11%, but did not affect low-density lipoprotein (LDL) cholesterol. Lipid distribution analysis through fast protein liquid chromatography indicated that COS significantly decreased TG content distributed in very-low-density lipoprotein (VLDL)/LDL fractions but increased cholesterol content in HDL fractions. Apolipoprotein analysis through plasma ultracentrifugation and sodium dodecyl sulfate polyacrylamide gel electrophoresis displayed that COS decreased apolipoprotein B-100 of LDL and increased apolipoprotein E of LDL and apolipoprotein B-100 of VLDL, but did not change apoA-I content of HDL particles. Lipoprotein formation associated protein determination showed that COS also increased plasma activity of lecithin cholesterol acyl transferase but not phospholipid transfer protein. The present study suggests that COS may play a beneficial role in plasma lipid regulation of rats with dyslipidemia induced by high-fat diet. The COS-decreased VLDL/LDL TG and -enhanced HDL cholesterol may be related to the upregulated activity of lecithin cholesterol acyl transferase.

  16. Minimal oxidation and storage of low density lipoproteins result in an increased susceptibility to phospholipid hydrolysis by phospholipase A2.

    PubMed

    Eckey, R; Menschikowski, M; Lattke, P; Jaross, W

    1997-07-25

    In vitro-studies have shown that phospholipid hydrolysis of low density lipoproteins (LDL) by bee venom or porcine pancreatic phospholipase A2 (PLA2) leads to an increased uptake of these lipoproteins by macrophages transforming them into foam cells. Recently, a secretory phospholipase A2, group II, was detected in human atherosclerotic plaques. In order to investigate the role of this enzyme in the pathogenesis of atherosclerosis, a structurally identical human secretory PLA2 was purified from the medium of HepG2 cells stimulated with interleukin-6 and tumor necrosis factor-alpha. The activity of the purified enzyme towards the phospholipids of native and modified low density lipoproteins was compared with the activity towards Escherichia coli-membranes and other phospholipid substrates. Compared to E. coli-membranes, native LDL proved to be a poor substrate for group II PLA2. After mild oxidation induced by copper ions or by 2,2-azobis(2-amidinopropane) (AAPH), the susceptibility of LDL to phospholipid hydrolysis was found to be increased by 25 and 23%, respectively, whereas extensive copper-mediated oxidation caused a decreased hydrolysis. Aging of LDL at 6 degrees C for weeks or at 37 degrees C for hours resulted in an increase in PLA2-catalyzed phospholipid hydrolysis of up to 26-fold. LDL protected from oxidation by probucol during aging showed a lesser increase in susceptibility to phospholipid hydrolysis. Our results suggest that PLA2, group II, can increase the atherogenicity of LDL by its ability to hydrolyze the phospholipids of these lipoproteins, especially after modifications that are likely to occur in vivo.

  17. Antagonism of Secreted PCSK9 Increases Low Density Lipoprotein Receptor Expression in HepG2 Cells

    SciTech Connect

    McNutt, Markey C.; Kwon, Hyock Joo; Chen, Chiyuan; Chen, Justin R.; Horton, Jay D.; Lagace, Thomas A.

    2009-07-10

    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.

  18. Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells.

    PubMed

    McNutt, Markey C; Kwon, Hyock Joo; Chen, Chiyuan; Chen, Justin R; Horton, Jay D; Lagace, Thomas A

    2009-04-17

    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.

  19. Nerve growth factor induces rapid increases in functional cell surface low density lipoprotein receptor-related protein.

    PubMed

    Bu, G; Sun, Y; Schwartz, A L; Holtzman, D M

    1998-05-22

    The low density lipoprotein receptor-related protein (LRP) is a large endocytic receptor that binds multiple ligands and is highly expressed in neurons. Several LRP ligands, including apolipoprotein E/lipoproteins and amyloid precursor protein, have been shown to participate either in Alzheimer's disease pathogenesis or pathology. However, factors that regulate LRP expression in neurons are unknown. In the current study, we analyzed the effects of nerve growth factor (NGF) treatment on LRP expression, distribution, and function within neurons in two neuronal cell lines. Our results show that NGF induces a rapid increase of cell surface LRP expression in a central nervous system-derived neuronal cell line, GT1-1 Trk, which was seen within 10 min and reached a maximum at about 1 h of NGF treatment. This increase of cell surface LRP expression is concomitant with an increase in the endocytic activity of LRP as measured via ligand uptake and degradation assays. We also found that the cytoplasmic tail of LRP is phosphorylated and that NGF rapidly increases the amount of phosphorylation. Furthermore, we detected a significant increase of LRP expression at the messenger RNA level following 24 h of NGF treatment. Both rapid and long term induction of LRP expression were also detected in peripheral nervous system-derived PC12 cells following NGF treatment. Taken together, our results demonstrate that NGF regulates LRP expression in neuronal cells.

  20. Fenofibrate Increases Very Low Density Lipoprotein Triglyceride Production Despite Reducing Plasma Triglyceride Levels in APOE*3-Leiden.CETP Mice*

    PubMed Central

    Bijland, Silvia; Pieterman, Elsbet J.; Maas, Annemarie C. E.; van der Hoorn, José W. A.; van Erk, Marjan J.; van Klinken, Jan B.; Havekes, Louis M.; van Dijk, Ko Willems; Princen, Hans M. G.; Rensen, Patrick C. N.

    2010-01-01

    The peroxisome proliferator-activated receptor alpha (PPARα) activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced very low density lipoprotein (VLDL)-TG clearance and decreased VLDL-TG production. However, because data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (−38%) and TG (−60%) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (−68%). This was associated with an increased post-heparin lipoprotein lipase (LPL) activity (+110%) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue, and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%) but not the VLDL-apolipoprotein B (apoB) production rate. Kinetic studies using [3H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma fatty acids and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver. PMID:20501652

  1. Fenofibrate increases very low density lipoprotein triglyceride production despite reducing plasma triglyceride levels in APOE*3-Leiden.CETP mice.

    PubMed

    Bijland, Silvia; Pieterman, Elsbet J; Maas, Annemarie C E; van der Hoorn, José W A; van Erk, Marjan J; van Klinken, Jan B; Havekes, Louis M; van Dijk, Ko Willems; Princen, Hans M G; Rensen, Patrick C N

    2010-08-13

    The peroxisome proliferator-activated receptor alpha (PPARalpha) activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced very low density lipoprotein (VLDL)-TG clearance and decreased VLDL-TG production. However, because data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%) and TG (-60%) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of glycerol tri[(3)H]oleate-labeled VLDL-like emulsion particles (-68%). This was associated with an increased post-heparin lipoprotein lipase (LPL) activity (+110%) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue, and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%) but not the VLDL-apolipoprotein B (apoB) production rate. Kinetic studies using [(3)H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma fatty acids and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver.

  2. Low-density lipoprotein apheresis: an overview.

    PubMed

    Bambauer, Rolf; Schiel, Ralf; Latza, Reinhard

    2003-08-01

    Atherosclerosis with myocardial infarction, stroke, and peripheral cellular disease still maintains its position at the top of morbidity and mortality statistics in industrialized nations. Established risk factors widely accepted are smoking, arterial hypertension, diabetes mellitus, and central obesity. Furthermore, there is a strong correlation between hyperlipidemia and atherosclerosis. The prognosis of patients suffering from severe hyperlipidemia, sometimes combined with elevated lipoprotein (a) (Lpa) levels, and coronary heart disease (CHD) refractory to diet and lipid-lowering drugs is poor. For such patients, regular treatment with low-density lipoprotein (LDL) apheresis is the therapeutic option. Today, there are four different LDL apheresis systems available: immunoadsorption, heparin-induced extracorporeal LDL/fibrinogen precipitation, dextran sulfate LDL adsorption and LDL hemoperfusion. Regarding the different LDL apheresis systems used, there is no significant difference with respect to the clinical outcome or concerning total cholesterol, LDL, high-density lipoprotein (HDL), or triglyceride concentrations. With respect to elevated Lpa levels, however, the immunoadsorption method seems to be the most effective. In 45 patients (25 women, 20 men) suffering from familial hypercholesterolemia resistant to diet and lipid lowering drugs, low-density lipoprotein (LDL) apheresis was performed over 95.6 +/- 44.7 months. Four different systems (Liposorber, 32 of 45, Kaneka, Osaka, Japan; Therasorb, 6 of 45, Baxter, Munich, Germany; Lipopak, 2 of 45, Pocard, Moscow, Russia; and Dali, 5 of 45, Fresenius, St. Wendel, Germany) were used. With all methods, average reductions of 57% for total cholesterol, 55.9% for LDL, 75.8% for lipoprotein a (Lpa), and 45.9% for triglycerides, and an average increase of 14.3% for HDL were reached. Severe side-effects such as shock or allergic reactions were very rare (0.3%) in all methods. In the course of treatment, an improvement

  3. Oxidized low density lipoprotein increases RANKL level in human vascular cells. Involvement of oxidative stress

    SciTech Connect

    Mazière, Cécile; Salle, Valéry; Gomila, Cathy; Mazière, Jean-Claude

    2013-10-18

    Highlights: •Oxidized LDL enhances RANKL level in human smooth muscle cells. •The effect of OxLDL is mediated by the transcription factor NFAT. •UVA, H{sub 2}O{sub 2} and buthionine sulfoximine also increase RANKL level. •All these effects are observed in human fibroblasts and endothelial cells. -- Abstract: Receptor Activator of NFκB Ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) have been shown to play a role not only in bone remodeling but also in inflammation, arterial calcification and atherosclerotic plaque rupture. In human smooth muscle cells, Cu{sup 2+}-oxidized LDL (CuLDL) 10–50 μg/ml increased reactive oxygen species (ROS) and RANKL level in a dose-dependent manner, whereas OPG level was not affected. The lipid extract of CuLDL reproduced the effects of the whole particle. Vivit, an inhibitor of the transcription factor NFAT, reduced the CuLDL-induced increase in RANKL, whereas PKA and NFκB inhibitors were ineffective. LDL oxidized by myeloperoxidase (MPO-LDL), or other pro-oxidant conditions such as ultraviolet A (UVA) irradiation, incubation with H{sub 2}O{sub 2} or with buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis{sub ,} also induced an oxidative stress and enhanced RANKL level. The increase in RANKL in pro-oxidant conditions was also observed in fibroblasts and endothelial cells. Since RANKL is involved in myocardial inflammation, vascular calcification and plaque rupture, this study highlights a new mechanism whereby OxLDL might, by generation of an oxidative stress, exert a deleterious effect on different cell types of the arterial wall.

  4. Low level of low-density lipoprotein cholesterol increases hemorrhagic transformation in large artery atherothrombosis but not in cardioembolism.

    PubMed

    Kim, Beom Joon; Lee, Seung-Hoon; Ryu, Wi-Sun; Kang, Bong Su; Kim, Chi Kyung; Yoon, Byung-Woo

    2009-05-01

    Low cholesterol level is known to be associated with increased cerebral hemorrhage. However, the associations of hemorrhagic transformation (HTf) after acute ischemic stroke and the low levels of total cholesterol (TC) or low-density lipoprotein cholesterol (LDLC) are largely undiscovered. Of the 1034 patients with acute ischemic stroke who were consecutively admitted to our hospital, 377 patients with stroke attributable to large artery atherothrombosis (LAA; n=210) or cardioembolism (n=167) were selected for this study. Demographic and clinical information was collected and HTf was evaluated through follow-up T2*-weighted gradient-echo MRI performed usually within 1 week after stroke. Measurement of lipid parameters included TC, LDLC, high-density lipoprotein cholesterol, and triglyceride. Of the 377 patients, HTf was noted in 74 patients (19.6%). When patients were divided into 4 groups according to their TC and LDLC levels, the incidence of HTf was significantly elevated in the lowest quartile of each TC (P<0.01) and LDLC (P<0.01) level in LAA subgroup, but not in cardioembolism. After adjusting covariates, a low level of LDLC (OR, 0.46 per 1 mmol/L-increase; 95% CI, 0.22-0.98) was independently associated with HTf in LAA, but not in cardioembolism. There was no significant association between low levels of TC (OR, 0.63 per 1 mmol/L-increase; 95% CI, 0.35-1.15) and HTf in LAA. Low levels of LDLC, and possibly TC, are associated with greater risk of hemorrhagic transformation after acute ischemic stroke attributable to LAA.

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

    PubMed

    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

    2014-01-01

    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 β-amyloidosis. In this regard, herein we hypothesized that the lack of LDLr would enhance the susceptibility to amyloid-β-(Aβ)-induced neurotoxicity in mice. Using the acute intracerebroventricular injection of aggregated Aβ(1-40) peptide (400 pmol/mouse), a useful approach for the investigation of molecular mechanisms involved in Aβ 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 Aβ treatment, displayed memory deficits and increased blood-brain barrier permeability. Nonetheless, LDLr(-/-) mice treated with Aβ(1-40) peptide presented increased acetylcholinesterase activity, astrogliosis, oxidative imbalance, and cell permeability within the hippocampus in comparison with Aβ(1-40)-treated C57BL/6 wild-type mice. Overall, the present study shows that the lack of LDLr increases the susceptibility to Aβ-induced neurotoxicity in mice providing new evidence about the crosslink between familial hypercholesterolemia and cognitive impairment.

  6. Rapid Increase in Serum Low-Density Lipoprotein Cholesterol Concentration during Hepatitis C Interferon-Free Treatment

    PubMed Central

    Abiru, Seigo; Komori, Atsumasa; Nagaoka, Shinya; Saeki, Akira; Uchida, Shinjiro; Bekki, Shigemune; Kugiyama, Yuki; Nagata, Kazuyoshi; Nakamura, Minoru; Migita, Kiyoshi; Nakao, Kazuhiko

    2016-01-01

    Background & Aim We performed lipid analyses at the early period of therapy in patients with chronic hepatitis C who underwent interferon (IFN)-free direct-acting antiviral (DAA) treatment, and we attempted to identify the factors that contributed to a rapid increase in the patients’ serum low-density lipoprotein cholesterol (LDL-C) concentration. Methods We retrospectively analyzed the cases of 100 consecutive patients with HCV infection treated at the National Hospital Organization Nagasaki Medical Center: 24 patients underwent daclatasvir (DCV) and asunaprevir (ASV) combination therapy (DCV/ASV) for 24 weeks, and the other 76 patients underwent ledipasvir and sofosbuvir combination therapy (LDV/SOF) for 12 weeks. ΔLDL-C was defined as the changed in LDL-C level at 28 days from the start of therapy. To determine whether ΔLDL-C was associated with several kinds of factors including viral kinetics, we performed a stepwise multiple linear regression analysis. Results The LDL-C levels in patients treated with LDV/SOF were markedly and significantly elevated (87.45 to 122.5 mg/dl; p<10−10) compared to those in the DCV/ASV-treated patients (80.15 to 87.8 mg/dl; p = 0.0056). The median levels of ΔLDL-C in the LDV/SOF and DCV/ASV groups were 33.2 and 13.1, respectively. LDV/SOF combination therapy as an IFN-free regimen (p<0.001) and ΔHCV core antigen (0–1 day drop) (p<0.044) were identified as independent factors that were closely related to the ΔLDL-C. Conclusions A rapid increase in the serum LDL-C concentration during the IFN-free treatment of hepatitis C was associated with the type of HCV therapy and a decline of HCV core protein. PMID:27680885

  7. Low-density lipoproteins oxidation and endometriosis.

    PubMed

    Polak, Grzegorz; Barczyński, Bartłomiej; Kwaśniewski, Wojciech; Bednarek, Wiesława; Wertel, Iwona; Derewianka-Polak, Magdalena; Kotarski, Jan

    2013-01-01

    The etiopathogenesis of endometriosis still remains unknown. Recent data provide new valuable information concerning the role of oxidative stress in the pathophysiology of the disease. It has been proved that levels of different lipid peroxidation end products are increased in both peritoneal fluid (PF) and serum of endometriotic patients. We assessed the concentration of oxidized low-density lipoproteins (oxLDL) in PF of 110 women with different stages of endometriosis and 119 women with serous (n = 78) or dermoid (n = 41) ovarian cysts, as the reference groups. PF oxLDL levels were evaluated by ELISA. We found that concentrations of oxLDL in PF of endometriotic women were significantly higher compared to women with serous but not dermoid ovarian cysts. Interestingly, by analyzing concentrations of oxLDL in women with different stages of the disease, it was noted that they are significantly higher only in the subgroup of patients with stage IV endometriosis as compared to women with ovarian serous cysts. In case of minimal, mild, and moderate disease, PF oxLDL levels were similar to those noted in reference groups. Our results indicate that disrupted oxidative status in the peritoneal cavity of women with endometriosis may play a role in the pathogenesis of advanced stages of the disease.

  8. 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)

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

    1984-04-01

    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.

  9. Electronegative Low-Density Lipoprotein Increases C-Reactive Protein Expression in Vascular Endothelial Cells through the LOX-1 Receptor

    PubMed Central

    Chu, Chih-Sheng; Wang, Yu-Chen; Lu, Long-Sheng; Walton, Brian; Yilmaz, H. Ramazan; Huang, Roger Y.; Sawamura, Tatsuya; Dixon, Richard A. F.; Lai, Wen-Ter; Chen, Chu-Huang; Lu, Jonathan

    2013-01-01

    Objectives Increased plasma C-reactive protein (CRP) levels are associated with the occurrence and severity of acute coronary syndrome. We investigated whether CRP can be generated in vascular endothelial cells (ECs) after exposure to the most electronegative subfraction of low-density lipoprotein (LDL), L5, which is atherogenic to ECs. Because L5 and CRP are both ligands for the lectin-like oxidized LDL receptor-1 (LOX-1), we also examined the role of LOX-1. Methods and Results Plasma LDL samples isolated from asymptomatic hypercholesterolemic (LDL cholesterol [LDL-C] levels, 154.6±20 mg/dL; n = 7) patients and normocholesterolemic (LDL-C levels, 86.1±21 mg/dL; P<0.001; n = 7) control individuals were chromatographically resolved into 5 subfractions, L1-L5. The L5 percentage (L5%) and the plasma L5 concentration ([L5]  =  L5% × LDL-C) in the patient and control groups were 8.1±2% vs. 2.3±1% (P<0.001) and 12.6±4 mg/dL vs. 1.9±1 mg/dL (P<0.001), respectively. In hypercholesterolemic patients treated with atorvastatin for 6 months (10 mg/day), [L5] decreased from 12.6±4 mg/dL to 4.5±1.1 mg/dL (P = 0.011; n = 5), whereas both [L5] and L5% returned to baseline levels in 2 noncompliant patients 3 months after discontinuation. In cultured human aortic ECs (HAECs), L5 upregulated CRP expression in a dose- and time-dependent manner up to 2.5-fold (P<0.01), whereas the least electronegative subfraction, L1, had no effect. DiI-labeled L1, internalized through the LDL receptor, became visible inside HAECs within 30 seconds. In contrast, DiI-labeled L5, internalized through LOX-1, became apparent after 5 minutes. L5-induced CRP expression manifested at 30 minutes and was attenuated by neutralizing LOX-1. After 30 minutes, L5 but not L1 induced reactive oxygen species (ROS) production. Both L5-induced ROS and CRP production were attenuated by ROS inhibitor N-acetyl cysteine. Conclusions Our results suggest that CRP, L5, and LOX-1 form a cyclic

  10. The aggressive low density lipoprotein lowering controversy.

    PubMed

    Forrester, J S; Bairey-Merz, C N; Kaul, S

    2000-10-01

    Recent clinical trials have provided unequivocal evidence of major cardiovascular benefits from low density lipoprotein (LDL) lowering with statins. However, the three critical unresolved questions about aggressive LDL lowering are the shape of the curve relating cardiac events to LDL, the best surrogate measurement for assessing therapeutic efficacy and the best target for LDL therapy. The relation between cardiac events and LDL is curvilinear, both epidemiologically and during therapy. The benefit of lipid lowering diminishes progressively and becomes difficult to detect at lower LDL levels without a very large sample size. Assessment of the benefits of lipid lowering is further confounded by differences in the level of pretreatment LDL and by the non-LDL lowering effects of statins. Both epidemiologic studies and large randomized clinical trials have produced conflicting results concerning the best LDL target. Failure to reduce the event rate in patients with pretreatment LDL <125 mg (Cholesterol And Recurrent Events [CARE] trial) alerts us to the risk of extrapolating epidemiologic data to clinical practice, yet subset analysis of some clinical trials suggests the greatest benefit appears in those patients with the lowest on-treatment LDL levels (Scandinavian Simvastatin Survival Study [4S]). This controversy should be resolved in the next few years by several important on-going trials. In the face of seemingly contradictory data from current clinical trials, we can only speculate that very aggressive LDL lowering to <80 mg/dl could be accompanied by a modest therapeutic benefit beyond the current recommendations of the National Cholesterol Education Program. If any benefit is observed, it will have to be balanced against a small potential for increased adverse events.

  11. Nerve growth factor (NGF) and pro-NGF increase low-density lipoprotein (LDL) receptors in neuronal cells partly by different mechanisms: role of LDL in neurite outgrowth.

    PubMed

    Do, Hai Thi; Bruelle, Céline; Pham, Dan Duc; Jauhiainen, Matti; Eriksson, Ove; Korhonen, Laura T; Lindholm, Dan

    2016-01-01

    Low-density lipoprotein receptors (LDLRs) mediate the uptake of lipoprotein particles into cells, as studied mainly in peripheral tissues. Here, we show that nerve growth factor (NGF) increases LDLR levels in PC6.3 cells and in cultured septal neurons from embryonic rat brain. Study of the mechanisms showed that NGF enhanced transcription of the LDLR gene, acting mainly via Tropomyosin receptor kinase A receptors. Simvastatin, a cholesterol-lowering drug, also increased the LDLR expression in PC6.3 cells. In addition, pro-NGF and pro-brain-derived neurotrophic factor, acting via the p75 neurotrophin receptor (p75NTR) also increased LDLRs. We further observed that Myosin Regulatory Light Chain-Interacting Protein/Inducible Degrader of the LDLR (Mylip/Idol) was down-regulated by pro-NGF, whereas the other LDLR regulator, proprotein convertase subtilisin kexin 9 (PCSK9) was not significantly changed. On the functional side, NGF and pro-NGF increased lipoprotein uptake by neuronal cells as shown using diacetyl-labeled LDL. The addition of serum-derived lipoprotein particles in conjunction with NGF or simvastatin enhanced neurite outgrowth. Collectively, these results show that NGF and simvastatin are able to stimulate lipoprotein uptake by neurons with a positive effect on neurite outgrowth. Increases in LDLRs and lipoprotein particles in neurons could play a functional role during brain development, in neuroregeneration and after brain injuries. Nerve growth factor (NGF) and pro-NGF induce the expression of low-density lipoprotein receptors (LDLRs) in neuronal cells leading to increased LDLR levels. Pro-NGF also down-regulated myosin regulatory light chain-interacting protein/inducible degrader of the LDLR (Mylip/Idol) that is involved in the degradation of LDLRs. NGF acts mainly via Tropomyosin receptor kinase A (TrkA) receptors, whereas pro-NGF stimulates p75 neurotrophin receptor (p75NTR). Elevated LDLRs upon NGF and pro-NGF treatments enhanced lipoprotein uptake

  12. [Control rate of increased low-density lipoprotein cholesterol levels in cardiology outpatients with coronary heart disease in Beijing].

    PubMed

    Ding, Rong-jing; Ma, Chang-sheng; Chen, Hong; Wu, Yan; Yang, Xin-chun; Hua, Qi; Li, Rui-jie; Ren, Wen-lin; Wang, Ming-sheng; Xiang, Xiao-ping; Du, Xin; Pi, Lin; Hu, Da-yi

    2013-03-01

    To investigate the low-density lipoprotein cholesterol (LDL-C) levels in outpatients with coronary heart disease (CHD) visiting cardiology outpatient clinics of 8 hospitals in Beijing. A total of 903 outpatients with CHD were enrolled from 4 three-tier hospitals and 4 two-tier hospitals in Beijing. All patients were asked to finish the questionnaire including demographic data, CHD history, the knowledge on cholesterol, and the use of statins. Blood lipid was examined and the LDL-C control rate and related factors were then analyzed. Questionnaire was obtained from 876 patients [619 male: 70.7%, mean age: (64.9 ± 10.7) years old] and blood lipid data were available in 709 patients. The general LDL-C control rate was 36.9% (262/709) and was 13.5% (27/173) in very high risk CHD patients, and lower in patients treated in two-tier hospitals than patients treated in three-tier hospitals[31.3% (121/386) vs. 43.7% (141/323), P < 0.01], in female patients than in male patients [27.1% (60/261) vs. 41.3% (201/496), P < 0.01] and in diabetic patients than in non-diabetic patients [13.5% (27/200) vs. 44.7% (197/441), P < 0.01]. The LDL-C control rate was lower in patients less than 60 years old and patients over 80 years old than that in 60-70 years old patients and 70 - 80 years old patients (P < 0.05). LDL-C control rate was not affected by the history of hypertension, percutaneous coronary intervention or coronary artery bypass grafting, smoking, lipid examination frequency, knowledge on goal level of LDL-C, diet control and regularly physical exercising (all P > 0.05). There were 18.2% (129/709) patients not taking statins or not aware if they were taking statin or not. The main reason for not taking statin [47.9% (23/48)] was statin was no prescribed by doctors, followed by withdrawal by patients due to various reasons [27.1% (13/48)]. LDL-C control rate was low in patients with CHD visiting cardiology outpatient clinics in Beijing. The CHD patients and cardiologists

  13. Testosterone increases the muscle protein synthesis rate but does not affect very-low-density lipoprotein metabolism in obese premenopausal women

    PubMed Central

    Wang, Xuewen; Smith, Gordon I.; Patterson, Bruce W.; Reeds, Dominic N.; Kampelman, Janine; Magkos, Faidon

    2012-01-01

    Men and women with hyperandrogenemia have a more proatherogenic plasma lipid profile [e.g., greater triglyceride (TG) and total and low-density lipoprotein-cholesterol and lower high-density lipoprotein-cholesterol concentrations] than healthy premenopausal women. Furthermore, castration of male rats markedly reduces testosterone availability below normal and decreases plasma TG concentration, and testosterone replacement reverses this effect. Testosterone is, therefore, thought to be an important regulator of plasma lipid homeostasis. However, little is known about the effect of testosterone on plasma TG concentration and kinetics. Furthermore, testosterone is a potent skeletal muscle protein anabolic agent in men, but its effect on muscle protein turnover in women is unknown. We measured plasma lipid concentrations, hepatic very low density lipoprotein (VLDL)-TG and VLDL-apolipoprotein B-100 secretion rates, and the muscle protein fractional synthesis rate in 10 obese women before and after trandermal testosterone (1.25 g of 1% AndroGel daily) treatment for 3 wk. Serum total and free testosterone concentrations increased (P < 0.05) by approximately sevenfold in response to testosterone treatment, reaching concentrations that are comparable to those in women with hyperandrogenemia, but lower than the normal range for eugonadal men. Except for a small (∼10%) decrease in plasma high-density lipoprotein particle and cholesterol concentrations (P < 0.04), testosterone therapy had no effect on plasma lipid concentrations, lipoprotein particle sizes, and hepatic VLDL-TG and VLDL-apolipoprotein B-100 secretion rates (all P > 0.05); the muscle protein fractional synthesis rate, however, increased by ∼45% (P < 0.001). We conclude that testosterone is a potent skeletal muscle protein anabolic agent, but not an important regulator of plasma lipid homeostasis in obese women. PMID:22252942

  14. Low density lipoprotein misfolding and amyloidogenesis.

    PubMed

    Parasassi, Tiziana; De Spirito, Marco; Mei, Giampiero; Brunelli, Roberto; Greco, Giulia; Lenzi, Laura; Maulucci, Giuseppe; Nicolai, Eleonora; Papi, Massimiliano; Arcovito, Giuseppe; Tosatto, Silvio C E; Ursini, Fulvio

    2008-07-01

    In early atherogenesis, subendothelial retention of lipidic droplets is associated with an inflammatory response-to-injury, culminating in the formation of foam cells and plaque. Low density lipoprotein (LDL) is the main constituent of subendothelial lipidic droplets. The process is believed to occur following LDL modification. Searching for a modified LDL in plasma, electronegative LDL [LDL(-)] was identified and found to be associated with major risk biomarkers. The apoprotein in LDL(-) is misfolded, and we show here that this modification primes the aggregation of native LDL, conforming to the typical pattern of protein amyloidogenesis. After a lag phase, whose length depends on LDL(-) concentration, light scattering and atomic force microscopy reveal early exponential growth of intermediate globules, which evolve into fibrils. These globules are remarkably similar to subendothelial droplets in atheromatous lesions and different from those produced by oxidation or biochemical manipulation. During aggregation, ellipticity and tryptophan fluorescence measurements reveal a domino-style spread of apoprotein misfolding from LDL(-) to all of the LDL. Computational analysis of the apoprotein primary sequence predicts an unstable, aggregation-prone domain in the regulatory alpha2 region. Apoprotein misfolding well represents an LDL modification able to transform this cholesterol carrier into a trigger for a response-to-injury in the artery wall.

  15. Adenovirus-mediated transfer of a gene encoding cholesterol 7 alpha-hydroxylase into hamsters increases hepatic enzyme activity and reduces plasma total and low density lipoprotein cholesterol.

    PubMed Central

    Spady, D K; Cuthbert, J A; Willard, M N; Meidell, R S

    1995-01-01

    Clinical interventions that accelerate conversion of cholesterol to bile acids reduce circulating low density lipoprotein (LDL) cholesterol concentrations. The initial and rate-limiting step in the bile acid biosynthetic pathway is catalyzed by hepatic cholesterol 7 alpha-hydroxylase. To examine the effects of transient primary overexpression of this enzyme on sterol metabolism and lipoprotein transport, we constructed a recombinant adenovirus in which a cDNA encoding rat 7 alpha-hydroxylase is expressed from the human cytomegalovirus immediate-early promoter (AdCMV7 alpha). Syrian hamsters administered AdCMV7 alpha intravenously accumulated transgene-specific mRNA in the liver and demonstrated a dose-dependent increase in hepatic microsomal 7 alpha-hydroxylase activity. The increased conversion of cholesterol to bile acids resulted in a compensatory increase in hepatic cholesterol synthesis. In addition, overexpression of 7 alpha-hydroxylase reduced the rate of LDL cholesterol entry into the plasma space and, in animals maintained on a Western-type diet, restored hepatic LDL receptor expression. As a consequence, plasma LDL concentrations fell by approximately 60% in animals maintained on control diet and by approximately 75% in animals consuming a Western-type diet. Plasma high density lipoprotein cholesterol levels were reduced to a lesser degree. These results demonstrate that transient upregulation of bile acid synthesis by direct transfer of a 7 alpha-hydroxylase gene favorably alters circulating lipoprotein profiles and suggest one potential molecular target for genetic strategies aimed at reducing cardiovascular risk. Images PMID:7635963

  16. Non-oxidative modification of native low-density lipoprotein by oxidized low-density lipoprotein.

    PubMed Central

    Yang, M; Leake, D S; Rice-Evans, C A

    1996-01-01

    The oxidative modification of low-density lipoprotein (LDL) has been implicated in the pathogenesis of atherosclerosis, although little is known as yet about the precise mechanism of oxidation in vivo. The studies presented here demonstrate that, in the absence of cells or transition metals, oxidized LDL can modify native LDL through co-incubation in vitro such as to increase its net negative charge, in a concentration-dependent manner. The interaction is not inhibited by peroxyl radical scavengers or metal chelators, precluding the possibility that the modification of native LDL by oxidized LDL is through an oxidative process. Studies with radioiodinated oxidized LDL showed no transfer of radioactivity to the native LDL, demonstrating that fragmentation of protein and the transfer of some of the fragments does not account for the modified charge on the native LDL particle. The adjacency of native to oxidized LDL in the arterial wall may be a potential mechanism by which the altered recognition properties of the apolipoprotein B-100 may arise rapidly without oxidation or extensive modification of the native LDL lipid itself. PMID:8687375

  17. Low-density lipoprotein density determination by electric conductivity.

    PubMed

    Fernández-Higuero, José A; Salvador, Ana M; Arrondo, José L R; Milicua, José Carlos G

    2011-10-15

    The predominance of small dense low-density lipoprotein (LDL) particles is associated with an increased risk of coronary heart disease. A simple but precise method has been developed, based on electrical conductivity of an isopycnic gradient of KBr, to obtain density values of human LDL fraction. The results obtained can distinguish LDL density populations and their subfractions from different patients. These data were corroborated by Fourier transform infrared spectroscopy (FTIR) (structure) and light-scattering analyses (size).

  18. Low density lipoproteins mediated nanoplatforms for cancer targeting

    NASA Astrophysics Data System (ADS)

    Jain, Anupriya; Jain, Keerti; Kesharwani, Prashant; Jain, Narendra K.

    2013-09-01

    Chemotherapy is a foremost remedial approach for the treatment of localized and metastasized tumors. In order to explore new treatment modalities for cancer, it is important to identify qualitative or quantitative differences in metabolic processes between normal and malignant cells. One such difference may be that of increased receptor-mediated cellular uptake of low density lipoproteins (LDLs) by cancer cells. Lipoproteins in general and specifically LDL are ideal candidates for loading and delivering cancer therapeutic and diagnostic agents due to their biocompatibility. By mimicking the endogenous shape and structure of lipoproteins, the reconstituted lipoproteins can remain in circulation for an extended period of time, while largely evading the reticuloendothelial cells in the body's defenses. In this account, we review the field of low density inspired nanoparticles in relation to the delivery of cancer imaging and therapeutic agents. LDL has instinctive cancer targeting potential and has been used to incorporate various lipophillic molecules to transport them to tumors. Nature's method of rerouting LDL provides a strategy to extend the cancer targeting potential of lipoproteins far off its constricted purview. In this review, we have discussed the various aspects of LDL including its role in cancer imaging and chemotherapy in retrospect and prospect and current efforts aimed to further improve the delivery efficacy of LDL-drug complexes with reduced chances of drug resistance leading to optimal drug delivery. This review provides a strong support for the concept of using LDL as a drug carrier.

  19. [Reducing low density lipoprotein-cholesterol levels by apheresis].

    PubMed

    Reiber, I; Gógl, A

    1994-03-13

    The predominate number of homozygote familial hypercholesterolemic and approximately 20% of heterozygotes are resistant to low cholesterol diet and lipid lowering pharmacological treatment even in combination of 2 or more drugs. In such cases, the selective lipoprotein apheresis has become a promising alternative and indicated absolute (homozygotes) or relative (heterozygotes). The combination of low density lipoprotein apheresis, together with diet and drugs, should allow a maximal lowering of low density lipoprotein-cholesterol (-60-70%). Besides low density lipoprotein, various apheresis procedures may also eliminate other potentially atherogenic factors, such as lipoprotein(a) and fibrinogen and acutely improve the haemo-rheological status of the patient. The authors review several lipoprotein apheresis procedures with varying degrees of selectivity, those have and furthermore analysis the advantages and disadvantages and cost of each procedure.

  20. Changes in plasma lipids and increased low-density lipoprotein susceptibility to oxidation in pregnancies complicated by gestational diabetes: consequences of obesity.

    PubMed

    Sánchez-Vera, Isabel; Bonet, Bartolome; Viana, Marta; Quintanar, Amalia; Martín, Maria D; Blanco, Pilar; Donnay, Sergio; Albi, Manuel

    2007-11-01

    Dyslipidemia is associated with increased low-density lipoprotein (LDL) susceptibility to oxidation, a phenomenon associated with endothelial dysfunction, atherosclerosis, cell toxicity, and intrauterine growth retardation. The present study was designed to determine if women developing gestational diabetes mellitus (GDM) have both increased plasma lipids and LDL susceptibility to oxidation throughout pregnancy. We also wanted to study the effects of obesity upon these parameters. A nested case-control study was carried out in 45 women with uncomplicated pregnancies and 62 women diagnosed with GDM following the criteria of the American Diabetes Association. In all women, blood was drawn at 15, 24, and 32 weeks of gestation. Low-density lipoprotein oxidation was initiated by the addition of CuCl2, and formation of conjugated dienes was monitored. Glucose, cholesterol, triglycerides, vitamin E, estradiol, and progesterone were determined. In GDM, elevated levels of glucose, cholesterol, and triglycerides were observed when compared with the control group even in the first trimester, before the detection of diabetes. In the control group, the lag phase in the LDL oxidation was 85.3, 84.4, and 95.6 minutes at 15, 24, and 32 weeks of pregnancy, compared with 63.3, 63.4, and 74.5 minutes in the GDM group (P < .001 in the 3 periods). These differences remained when adjusted for the body mass index. In a multiple linear regression analysis, a negative correlation was observed between the lag phase and the body mass index (P < .001) and cholesterol (P < .001), whereas a positive one appeared with vitamin E (P < .05) and time of gestation (P < .001). In pregnancy, GDM increases LDL susceptibility to oxidation. Obesity and hypercholesterolemia further exacerbate this effect.

  1. Additional consumption of one egg per day increases serum lutein plus zeaxanthin concentration and lowers oxidized low-density lipoprotein in moderately hypercholesterolemic males.

    PubMed

    Kishimoto, Yoshimi; Taguchi, Chie; Saita, Emi; Suzuki-Sugihara, Norie; Nishiyama, Hiroshi; Wang, Wei; Masuda, Yasunobu; Kondo, Kazuo

    2017-09-01

    The egg is a nutrient-dense food and contains antioxidative carotenoids, lutein and zeaxanthin, but its impact on serum cholesterol levels has been a matter of concern, especially for individuals who have high serum cholesterol levels. We conducted this study to determine whether and how the daily additional consumption of one egg affects serum lipid profiles and parameters of LDL oxidation in moderately hypercholesterolemic males. Nineteen male Japanese adults (total cholesterol [TC]>5.2mmol/L) participated, consuming one soft boiled egg per day for 4weeks in addition to their habitual diet. Despite the significant increase in their intake of dietary cholesterol during the intervention period, the subjects' serum concentrations of TC and low-density lipoprotein cholesterol (LDL-C) did not increase. Their serum malondialdehyde modified low-density lipoprotein (MDA-LDL) concentrations were significantly decreased and their LDL oxidation lag times, reflecting the resistance of free-radical-induced LDL lipid peroxidation (ex vivo), was prolonged after 2 and 4weeks. At weeks 2 and 4, the subjects' serum lutein+zeaxanthin concentrations were significantly higher than their baseline values and showed both an inverse relation with MDA-LDL and a positive relationship with the LDL oxidation lag time. These data showed that in moderately hypercholesterolemic males, the additional consumption of one egg per day for 4weeks did not have adverse effects on serum TC or LDL-C, and it might reduce the susceptibility of LDL to oxidation through an increase in the serum lutein and zeaxanthin concentrations. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    PubMed Central

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

    2014-01-01

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

  3. 21 CFR 866.5600 - Low-density lipoprotein immunological test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Low-density lipoprotein immunological test system....5600 Low-density lipoprotein immunological test system. (a) Identification. A low-density lipoprotein... the low-density lipoprotein in serum and other body fluids. Measurement of low-density lipoprotein...

  4. 21 CFR 866.5600 - Low-density lipoprotein immunological test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Low-density lipoprotein immunological test system....5600 Low-density lipoprotein immunological test system. (a) Identification. A low-density lipoprotein... the low-density lipoprotein in serum and other body fluids. Measurement of low-density lipoprotein...

  5. Echium oil reduces plasma triglycerides by increasing intravascular lipolysis in apoB100-only low density lipoprotein (LDL) receptor knockout mice.

    PubMed

    Forrest, Lolita M; Lough, Christopher M; Chung, Soonkyu; Boudyguina, Elena Y; Gebre, Abraham K; Smith, Thomas L; Colvin, Perry L; Parks, John S

    2013-07-12

    Echium oil (EO), which is enriched in SDA (18:4 n-3), reduces plasma triglyceride (TG) concentrations in humans and mice. We compared mechanisms by which EO and fish oil (FO) reduce plasma TG concentrations in mildly hypertriglyceridemic male apoB100-only LDLrKO mice. Mice were fed one of three atherogenic diets containing 0.2% cholesterol and palm oil (PO; 20%), EO (10% EO + 10% PO), or FO (10% FO + 10% PO). Livers from PO- and EO-fed mice had similar TG and cholesteryl ester (CE) content, which was significantly higher than in FO-fed mice. Plasma TG secretion was reduced in FO vs. EO-fed mice. Plasma very low density lipoprotein (VLDL) particle size was ordered: PO (63 ± 4 nm) > EO (55 ± 3 nm) > FO (40 ± 2 nm). Post-heparin lipolytic activity was similar among groups, but TG hydrolysis by purified lipoprotein lipase was significantly greater for EO and FO VLDL compared to PO VLDL. Removal of VLDL tracer from plasma was marginally faster in EO vs. PO fed mice. Our results suggest that EO reduces plasma TG primarily through increased intravascular lipolysis of TG and VLDL clearance. Finally, EO may substitute for FO to reduce plasma TG concentrations, but not hepatic steatosis in this mouse model.

  6. Echium Oil Reduces Plasma Triglycerides by Increasing Intravascular Lipolysis in apoB100-Only Low Density Lipoprotein (LDL) Receptor Knockout Mice

    PubMed Central

    Forrest, Lolita M.; Lough, Christopher M.; Chung, Soonkyu; Boudyguina, Elena Y.; Gebre, Abraham K.; Smith, Thomas L.; Colvin, Perry L.; Parks, John S.

    2013-01-01

    Echium oil (EO), which is enriched in SDA (18:4 n-3), reduces plasma triglyceride (TG) concentrations in humans and mice. We compared mechanisms by which EO and fish oil (FO) reduce plasma TG concentrations in mildly hypertriglyceridemic male apoB100-only LDLrKO mice. Mice were fed one of three atherogenic diets containing 0.2% cholesterol and palm oil (PO; 20%), EO (10% EO + 10% PO), or FO (10% FO + 10% PO). Livers from PO- and EO-fed mice had similar TG and cholesteryl ester (CE) content, which was significantly higher than in FO-fed mice. Plasma TG secretion was reduced in FO vs. EO-fed mice. Plasma very low density lipoprotein (VLDL) particle size was ordered: PO (63 ± 4 nm) > EO (55 ± 3 nm) > FO (40 ± 2 nm). Post-heparin lipolytic activity was similar among groups, but TG hydrolysis by purified lipoprotein lipase was significantly greater for EO and FO VLDL compared to PO VLDL. Removal of VLDL tracer from plasma was marginally faster in EO vs. PO fed mice. Our results suggest that EO reduces plasma TG primarily through increased intravascular lipolysis of TG and VLDL clearance. Finally, EO may substitute for FO to reduce plasma TG concentrations, but not hepatic steatosis in this mouse model. PMID:23857172

  7. Intrauterine growth restriction combined with a maternal high-fat diet increases hepatic cholesterol and low-density lipoprotein receptor activity in rats.

    PubMed

    Zinkhan, Erin K; Zalla, Jennifer M; Carpenter, Jeanette R; Yu, Baifeng; Yu, Xing; Chan, Gary; Joss-Moore, Lisa; Lane, Robert H

    2016-07-01

    Intrauterine growth restriction (IUGR) and maternal consumption of a high-saturated-fat diet (HFD) increase the risk of hypercholesterolemia, a leading cause of morbidity and mortality. Many pregnant women eat a HFD, thus exposing the fetus to a HFD in utero. The cumulative effect of in utero exposure to IUGR and a HFD on offspring cholesterol levels remains unknown. Furthermore, little is known about the mechanism through which IUGR and maternal HFD consumption increase cholesterol. We hypothesize that IUGR combined with a maternal HFD would increase offspring serum and hepatic cholesterol accumulation via alteration in levels of key proteins involved in cholesterol metabolism. To test our hypothesis we used a rat model of surgically induced IUGR and fed the dams a regular diet or a HFD HFD-fed dams consumed the same kilocalories as regular diet-fed dams, with no difference between surgical intervention groups. In the offspring, IUGR combined with a maternal HFD increased hepatic cholesterol levels, low-density lipoprotein (LDL) receptor protein levels, and Ldlr activity in female rat offspring at birth and both sexes at postnatal day 14 relative to non-IUGR offspring both from regular diet- and HFD-fed dams. These findings suggest that IUGR combined with a maternal HFD increases hepatic cholesterol accumulation via increased LDL cholesterol uptake into the liver with resulting persistent increases in hepatic cholesterol accumulation.

  8. Exercise significantly increases plasma adrenaline and oxidized low-density lipoprotein in normal healthy subjects but not in persons with spinal cord injury.

    PubMed

    Mitsui, Toshihito; Nakamura, Takeshi; Ito, Tomoyuki; Umemoto, Yasunori; Sakamoto, Keiko; Kinoshita, Tokio; Nakagawa, Masafumi; Tajima, Fumihiro

    2012-04-01

    To compare plasma concentrations of oxidized low-density lipoprotein (oxLDL) and adrenaline during exercise between persons with spinal cord injury (SCI) and able-bodied (AB) individuals. Randomized controlled study. Human laboratory at a medical university. Persons with SCI (n=7) and AB individuals (n=9). Two-hour arm crank ergometer exercise at 60% maximum oxygen consumption. Plasma oxLDL and adrenaline levels. Exercise significantly increased plasma adrenaline levels in AB persons (mean ± SD: rest, 45.4±32.2 pg/mL; exercise, 200.9±113.7 pg/mL; P<.05) and persons with SCI; however; the magnitude of the increase in those with SCI was attenuated (mean ± SD: rest, 45.4±14.0 pg/mL; exercise, 83.0±55.8 pg/mL; P<.05). Exercise also significantly increased plasma oxLDL levels in AB persons (mean ± SD: rest, 102.2±30.2 U/L; exercise, 179.7±60.0 U/L; P<.05), but not in persons with SCI (mean ± SD: rest, 124.3±66.0 U/L; exercise, 138.9±59.5 U/L). The results suggest that increases in plasma adrenaline levels during exercise contribute to the increase in plasma oxLDL levels. Copyright © 2012 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  9. Interferon-Free Treatment of Hepatitis C Virus in HIV/Hepatitis C Virus-Coinfected Subjects Results in Increased Serum Low-Density Lipoprotein Concentration

    PubMed Central

    Townsend, Kerry; Meissner, Eric G.; Sidharthan, Sreetha; Sampson, Maureen; Remaley, Alan T.; Tang, Lydia; Kohli, Anita; Osinusi, Anu; Masur, Henry

    2016-01-01

    Abstract Chronic hepatitis C virus (HCV) infection is associated with lower serum concentration of low-density lipoprotein (LDL-C), the primary cholesterol metabolite targeted pharmaceutically to modulate cardiovascular risk. Chronic infection with human immunodeficiency virus (HIV) and treatment with antiretrovirals (ARVs) are associated with dyslipidemia and increased risk of cardiovascular disease. In subjects coinfected with HIV and HCV, lipid abnormalities associated with either infection alone are often attenuated. Treatment of chronic HCV infection in HIV/HCV-coinfected subjects is now possible with interferon (IFN)-free regimens composed of directly acting antivirals (DAAs). We previously observed a marked increase in serum LDL-C in HCV-monoinfected subjects treated with sofosbuvir and ribavirin (SOF/RBV) that correlated with viral decline in serum, suggesting a direct influence of HCV clearance on serum cholesterol. In the present study, we assessed longitudinal changes in cholesterol in HIV/HCV-coinfected subjects during treatment of HCV genotype-1 (GT1) infection with combination DAA therapy. We report a rapid increase in LDL-C and LDL particle size by week 2 of treatment that was sustained during and after treatment in HIV/HCV-coinfected subjects. No change in serum LDL-C was observed at day 3 of treatment, in spite of a marked reduction in serum HCV viral load, suggesting LDL-C increases do not directly reflect HCV clearance as measured in peripheral blood. After effective DAA therapy for HCV, an increase in LDL should be anticipated in HIV/HCV-coinfected subjects. PMID:26559180

  10. Managing to low-density lipoprotein particles compared with low-density lipoprotein cholesterol: a cost-effectiveness analysis.

    PubMed

    Rizzo, John A; Mallow, Peter J; Waters, Heidi C; Pokrywka, Gregory S

    2013-01-01

    Meta-analyses of clinical trials have shown that using statins to lower low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular events, and more intensive lowering of LDL-C further decreases the risk of occlusive vascular events. Lipoprotein studies suggest treating patients more aggressively when low-density lipoprotein particle (LDL-P) number is discordantly high in the presence of normal LDL-C levels. Failure to manage LDL-P numbers may lead to additional direct and indirect costs. This analysis modeled direct and indirect costs associated with cardiovascular events due to suboptimal treatment resulting from discordance between LDL-C and LDL-P levels. The analysis was conducted from the payer perspective and the employer perspective, respectively, over a 3-year time period. Clinical data were obtained from the Multi-Ethnic Study of Atherosclerosis, a community-based population study. The employer perspective included indirect costs and quality-adjusted life years in addition to the direct costs and cardiovascular disease events considered in the payer analysis. All costs are reported in 2011 dollars. From the payer perspective, managing LDL-C and LDL-P in comparison with LDL-C alone reduced costs ($21,212) and cardiovascular events (9 events). Similar patterns were observed for managing LDL-P alone in comparison with LDL-C. From the employer perspective, managing both LDL-P alone or in combination with LDL-C also resulted in lower costs, fewer cardiovascular disease events, and increased quality-adjusted life years in comparison with LDL-C. This analysis indicates that the benefits of additional testing to optimally manage LDL-P levels outweigh the costs of more aggressive treatment. These favorable results depended on the cost of drug therapy. Copyright © 2013 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  11. Dietary non-tocopherol antioxidants present in extra virgin olive oil increase the resistance of low density lipoproteins to oxidation in rabbits.

    PubMed

    Wiseman, S A; Mathot, J N; de Fouw, N J; Tijburg, L B

    1996-02-01

    Consumption of a range of dietary antioxidants may be beneficial in protecting low density lipoprotein (LDL) against oxidative modification, as studies have demonstrated that antioxidants other than vitamin E may also function against oxidation of LDL in vitro. In the present study, the effect of polyphenol antioxidants on the susceptibility of LDL to copper-mediated oxidation was investigated after feeding semi-purified diets to 3 groups of New Zealand white (NZW) rabbits. All diets comprised 40% energy as fat with 17% energy as oleic acid. Dietary fatty acid compositions were identical. Oils with different polyphenol contents were used to provide the dietary source of oleic acid-refined olive oil, extra virgin olive oil and Trisun high oleic sunflower seed oil. Polyphenolic compounds (hydroxytyrosol and p-tyrosol) could only be detected in the extra virgin olive oil. Vitamin E was equalised in all diets. LDL oxidizability in vitro was determined by continuously monitoring the copper-induced formation of conjugated dienes after 6 weeks of experimental diet feeding. The lag phase before demonstrable oxidation occurred was significantly increased in the high polyphenol, extra virgin olive oil group (P < 0.05) when compared with combined results from the low polyphenol group (refined olive oil and Trisun), even though the LDL vitamin E concentration in the high polyphenol group was significantly lower. The rate of conjugated diene formation was not influenced by the presence of dietary polyphenols. Results demonstrate that antioxidants, possibly phenolic compounds which are present only in extra virgin olive oil, may contribute to the endogenous antioxidant capacity of LDL, resulting in an increased resistance to oxidation as determined in vitro.

  12. Effect of atorvastatin on postcardiac transplant increase in low-density lipoprotein cholesterol reduces development of intimal hyperplasia and progression of endothelial dysfunction.

    PubMed

    See, Vincent Y; DeNofrio, David; Goldberg, Lee; Chang, Gene; Sasseen, Brett; Kolansky, Daniel M; Pickering, Faith; Kao, Andrew; Loh, Evan; Wilensky, Robert L

    2003-07-01

    Following cardiac transplantation, accelerated coronary disease limits long-term survival. Because statins may reduce the progression of the disease in part by their anti-inflammatory effects, this study was designed to assess if atorvastatin prevented neointimal hyperplasia and endothelial dysfunction independently of baseline cholesterol levels. Patients were randomized to usual therapy (n = 13) or to 10 to 20 mg of atorvastatin (n = 12). Control subjects received niacin when their low-density lipoprotein (LDL) cholesterol levels were >130 mg/dl (n = 4). Neointimal hyperplasia by intracoronary ultrasonography, endothelial dependent vascular reactivity, and coronary flow reserve were measured at baseline and 1 year. Control group total cholesterol (203 +/- 11 to 200 +/- 13 mg/dl) and LDL (116 +/- 10 to 119 +/- 11 mg/dl) remained stable, whereas there was a nonsignificant reduction at 12 months in the atorvastatin group (total cholesterol 216 +/- 28 to 178 +/- 21 mg/dl; LDL 126 +/- 17 to 100 +/- 18 mg/dl). At 2 to 3 months there was a significant increase in total cholesterol and LDL cholesterol that was reduced with atorvastatin. At 1 year, patients taking atorvastatin showed a decrease in new or progressing lesions (2.5 +/- 1.7 vs 4.2 +/- 1.8 lesions/patient, p = 0.02), progression of maximal intimal thickness (0.12 +/- 0.07 vs 0.52 +/- 0.17 mm, p = 0.04), and percent area stenosis (5.9 +/- 2.2% vs 19.0 +/- 5.5%, p = 0.04). Atorvastatin ameliorated progressive endothelial dysfunction, whereas coronary flow reserve was unchanged in both groups. Atorvastatin administered to patients with normal or mild hypercholesterolemia in the initial year after transplant reduced the initial increase in LDL cholesterol, and, by doing so, prevented the development and progression of coronary artery lesions and endothelial dysfunction with only mild long-term decreases in cholesterol levels.

  13. Thermal stability of human plasma electronegative low-density lipoprotein: A paradoxical behavior of low-density lipoprotein aggregation

    PubMed Central

    Rull, Anna; Jayaraman, Shobini; Gantz, Donald L.; Rivas-Urbina, Andrea; Pérez-Cuellar, Montserrat; Ordóñez-Llanos, Jordi; Sánchez-Quesada, Jose Luis; Gursky, Olga

    2017-01-01

    Low-density lipoprotein (LDL) aggregation is central in triggering atherogenesis. A minor fraction of electronegative plasma LDL, termed LDL(−), plays a special role in atherogenesis. To better understand this role, we analyzed the kinetics of aggregation, fusion and disintegration of human LDL and its fractions, LDL(+) and LDL(−). Thermal denaturation of LDL was monitored by spectroscopy and electron microscopy. Initially, LDL(−) aggregated and fused faster than LDL(+), but later the order reversed. Most LDL(+) disintegrated and precipitated upon prolonged heating. In contrast, LDL(−) partially retained lipoprotein morphology and formed soluble aggregates. Biochemical analysis of all fractions showed no significant degradation of major lipids, mild phospholipid oxidation, and anincrease in non-esterified fatty acid (NEFA) upon thermal denaturation. The main baseline difference between LDL subfractions was higher content of NEFA in LDL(−). Since NEFA promote lipoprotein fusion, increased NEFA content can explain rapid initial aggregation and fusion of LDL(−) but not its resistance to extensive disintegration. Partial hydrolysis of apoB upon heating was similar in LDL subfractions, suggesting that minor proteins importantly modulate LDL disintegration. Unlike LDL(+), LDL(−) contains small amounts of apoA-I and apoJ. Addition of exogenous apoA-I to LDL(+) hampered lipoprotein aggregation, fusion and precipitation, while depletion of endogenous apoJ had an opposite effect. Therefore, the initial rapid aggregation of LDL(−) is apparently counterbalanced by the stabilizing effects of minor proteins such as apoA-I and apoJ. These results help identify key determinants for LDL aggregation, fusion and coalescence into lipid droplets in vivo. PMID:27233433

  14. Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine–homocysteine S-methyltransferase

    PubMed Central

    Sparks, Janet D.; Collins, Heidi L.; Chirieac, Doru V.; Cianci, Joanne; Jokinen, Jenny; Sowden, Mark P.; Galloway, Chad A.; Sparks, Charles E.

    2006-01-01

    We have previously reported a positive correlation between the expression of BHMT (betaine–homocysteine S-methyltransferase) and ApoB (apolipoprotein B) in rat hepatoma McA (McArdle RH-7777) cells [Sowden, Collins, Smith, Garrow, Sparks and Sparks (1999) Biochem. J. 341, 639–645]. To examine whether a similar relationship occurs in vivo, hepatic BHMT expression was induced by feeding rats a Met (L-methionine)-restricted betaine-containing diet, and parameters of ApoB metabolism were evaluated. There were no generalized metabolic abnormalities associated with Met restriction for 7 days, as evidenced by control levels of serum glucose, ketones, alanine aminotransferase and L-homocysteine levels. Betaine plus the Met restriction resulted in lower serum insulin and non-esterified fatty acid levels. Betaine plus Met restriction induced hepatic BHMT 4-fold and ApoB mRNA 3-fold compared with Met restriction alone. No changes in percentage of edited ApoB mRNA were observed on the test diets. An increase in liver ApoB mRNA correlated with an 82% and 46% increase in ApoB and triacylglycerol production respectively using in vivo Triton WR 1339. Increased secretion of VLDL (very-low-density lipoprotein) with Met restriction plus betaine was associated with a 45% reduction in liver triacylglycerol compared with control. Nuclear run-off assays established that transcription of both bhmt and apob genes was also increased in Met-restricted plus betaine diets. No change in ApoB mRNA stability was detected in BHMT-transfected McA cells. Hepatic ApoB and BHMT mRNA levels were also increased by 1.8- and 3-fold respectively by betaine supplementation of Met-replete diets. Since dietary betaine increased ApoB mRNA, VLDL ApoB and triacylglycerol production and decreased hepatic triacylglycerol, results suggest that induction of apob transcription may provide a potential mechanism for mobilizing hepatic triacylglycerol by increasing ApoB available for VLDL assembly and secretion

  15. Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine-homocysteine S-methyltransferase.

    PubMed

    Sparks, Janet D; Collins, Heidi L; Chirieac, Doru V; Cianci, Joanne; Jokinen, Jenny; Sowden, Mark P; Galloway, Chad A; Sparks, Charles E

    2006-04-15

    We have previously reported a positive correlation between the expression of BHMT (betaine-homocysteine S-methyltransferase) and ApoB (apolipoprotein B) in rat hepatoma McA (McArdle RH-7777) cells [Sowden, Collins, Smith, Garrow, Sparks and Sparks (1999) Biochem. J. 341, 639-645]. To examine whether a similar relationship occurs in vivo, hepatic BHMT expression was induced by feeding rats a Met (L-methionine)-restricted betaine-containing diet, and parameters of ApoB metabolism were evaluated. There were no generalized metabolic abnormalities associated with Met restriction for 7 days, as evidenced by control levels of serum glucose, ketones, alanine aminotransferase and L-homocysteine levels. Betaine plus the Met restriction resulted in lower serum insulin and non-esterified fatty acid levels. Betaine plus Met restriction induced hepatic BHMT 4-fold and ApoB mRNA 3-fold compared with Met restriction alone. No changes in percentage of edited ApoB mRNA were observed on the test diets. An increase in liver ApoB mRNA correlated with an 82% and 46% increase in ApoB and triacylglycerol production respectively using in vivo Triton WR 1339. Increased secretion of VLDL (very-low-density lipoprotein) with Met restriction plus betaine was associated with a 45% reduction in liver triacylglycerol compared with control. Nuclear run-off assays established that transcription of both bhmt and apob genes was also increased in Met-restricted plus betaine diets. No change in ApoB mRNA stability was detected in BHMT-transfected McA cells. Hepatic ApoB and BHMT mRNA levels were also increased by 1.8- and 3-fold respectively by betaine supplementation of Met-replete diets. Since dietary betaine increased ApoB mRNA, VLDL ApoB and triacylglycerol production and decreased hepatic triacylglycerol, results suggest that induction of apob transcription may provide a potential mechanism for mobilizing hepatic triacylglycerol by increasing ApoB available for VLDL assembly and secretion.

  16. Increased beta-amyloid levels in the choroid plexus following lead exposure and the involvement of low-density lipoprotein receptor protein-1.

    PubMed

    Behl, Mamta; Zhang, Yanshu; Monnot, Andrew D; Jiang, Wendy; Zheng, Wei

    2009-10-15

    The choroid plexus, a barrier between the blood and cerebrospinal fluid (CSF), is known to accumulate lead (Pb) and also possibly function to maintain brain's homeostasis of Abeta, an important peptide in the etiology of Alzheimer's disease. This study was designed to investigate if Pb exposure altered Abeta levels at the blood-CSF barrier in the choroid plexus. Rats received ip injection of 27 mg Pb/kg. Twenty-four hours later, a FAM-labeled Abeta (200 pmol) was infused into the lateral ventricle and the plexus tissues were removed to quantify Abeta accumulation. Results revealed a significant increase in intracellular Abeta accumulation in the Pb-exposed animals compared to controls (p<0.001). When choroidal epithelial Z310 cells were treated with 10 microM Pb for 24 h and 48 h, Abeta (2 microM in culture medium) accumulation was significantly increased by 1.5 fold (p<0.05) and 1.8 fold (p<0.05), respectively. To explore the mechanism, we examined the effect of Pb on low-density lipoprotein receptor protein-1 (LRP1), an intracellular Abeta transport protein. Following acute Pb exposure with the aforementioned dose regimen, levels of LRP1 mRNA and proteins in the choroid plexus were decreased by 35% (p<0.05) and 31.8% (p<0.05), respectively, in comparison to those of controls. In Z310 cells exposed to 10 microM Pb for 24 h and 48 h, a 33.1% and 33.4% decrease in the protein expression of LRP1 was observed (p<0.05), respectively. Knocking down LRP1 resulted in even more substantial increases of cellular accumulation of Abeta, from 31% in cells without knockdown to 72% in cells with LRP1 knockdown (p<0.05). Taken together, these results suggest that the acute exposure to Pb results in an increased accumulation of intracellular Abeta in the choroid plexus; the effect appears to be mediated, at least in part, via suppression of LRP1 production following Pb exposure.

  17. Increased {beta}-amyloid levels in the choroid plexus following lead exposure and the involvement of low-density lipoprotein receptor protein-1

    SciTech Connect

    Behl, Mamta; Zhang Yanshu; Monnot, Andrew D.; Jiang, Wendy; Zheng Wei

    2009-10-15

    The choroid plexus, a barrier between the blood and cerebrospinal fluid (CSF), is known to accumulate lead (Pb) and also possibly function to maintain brain's homeostasis of A{beta}, an important peptide in the etiology of Alzheimer's disease. This study was designed to investigate if Pb exposure altered A{beta} levels at the blood-CSF barrier in the choroid plexus. Rats received ip injection of 27 mg Pb/kg. Twenty-four hours later, a FAM-labeled A{beta} (200 pmol) was infused into the lateral ventricle and the plexus tissues were removed to quantify A{beta} accumulation. Results revealed a significant increase in intracellular A{beta} accumulation in the Pb-exposed animals compared to controls (p < 0.001). When choroidal epithelial Z310 cells were treated with 10 {mu}M Pb for 24 h and 48 h, A{beta} (2 {mu}M in culture medium) accumulation was significantly increased by 1.5 fold (p < 0.05) and 1.8 fold (p < 0.05), respectively. To explore the mechanism, we examined the effect of Pb on low-density lipoprotein receptor protein-1 (LRP1), an intracellular A{beta} transport protein. Following acute Pb exposure with the aforementioned dose regimen, levels of LRP1 mRNA and proteins in the choroid plexus were decreased by 35% (p < 0.05) and 31.8% (p < 0.05), respectively, in comparison to those of controls. In Z310 cells exposed to 10 {mu}M Pb for 24 h and 48 h, a 33.1% and 33.4% decrease in the protein expression of LRP1 was observed (p < 0.05), respectively. Knocking down LRP1 resulted in even more substantial increases of cellular accumulation of A{beta}, from 31% in cells without knockdown to 72% in cells with LRP1 knockdown (p < 0.05). Taken together, these results suggest that the acute exposure to Pb results in an increased accumulation of intracellular A{beta} in the choroid plexus; the effect appears to be mediated, at least in part, via suppression of LRP1 production following Pb exposure.

  18. Fat utilization during exercise: adaptation to a fat-rich diet increases utilization of plasma fatty acids and very low density lipoprotein-triacylglycerol in humans

    PubMed Central

    Helge, Jørn W; Watt, Peter W; Richter, Erik A; Rennie, Michael J; Kiens, Bente

    2001-01-01

    This study was carried out to test the hypothesis that the greater fat oxidation observed during exercise after adaptation to a high-fat diet is due to an increased uptake of fat originating from the bloodstream. Of 13 male untrained subjects, seven consumed a fat-rich diet (62% fat, 21% carbohydrate) and six consumed a carbohydrate-rich diet (20% fat, 65% carbohydrate). After 7 weeks of training and diet, 60 min of bicycle exercise was performed at 68 ± 1% of maximum oxygen uptake. During exercise [1-13C]palmitate was infused, arterial and venous femoral blood samples were collected, and blood flow was determined by the thermodilution technique. Muscle biopsy samples were taken from the vastus lateralis muscle before and after exercise. During exercise, the respiratory exchange ratio was significantly lower in subjects consuming the fat-rich diet (0.86 ± 0.01, mean ±s.e.m.) than in those consuming the carbohydrate-rich diet (0.93 ± 0.02). The leg fatty acid (FA) uptake (183 ± 37 vs. 105 ± 28 μmol min−1) and very low density lipoprotein-triacylglycerol (VLDL-TG) uptake (132 ± 26 vs. 16 ± 21 μmol min−1) were both higher (each P < 0.05) in the subjects consuming the fat-rich diet. Whole-body plasma FA oxidation (determined by comparison of 13CO2 production and blood palmitate labelling) was 55-65% of total lipid oxidation, and was higher after the fat-rich diet than after the carbohydrate-rich diet (13.5 ± 1.2 vs. 8.9 ± 1.1 μmol min−1 kg−1; P < 0.05). Muscle glycogen breakdown was significantly lower in the subjects taking the fat-rich diet than those taking the carbohydrate-rich diet (2.6 ± 0.5 vs. 4.8 ± 0.5 mmol (kg dry weight)−1 min−1, respectively; P < 0.05), whereas leg glucose uptake was similar (1.07 ± 0.13 vs. 1.15 ± 0.13 mmol min−1). In conclusion, plasma VLDL-TG appears to be an important substrate source during aerobic exercise, and in combination with the higher plasma FA uptake it accounts for the increased fat oxidation

  19. Low-Density Lipoprotein Receptor-Dependent and Low-Density Lipoprotein Receptor-Independent Mechanisms of Cyclosporin A-Induced Dyslipidemia.

    PubMed

    Kockx, Maaike; Glaros, Elias; Leung, Betty; Ng, Theodore W; Berbée, Jimmy F P; Deswaerte, Virginie; Nawara, Diana; Quinn, Carmel; Rye, Kerry-Anne; Jessup, Wendy; Rensen, Patrick C N; Meikle, Peter J; Kritharides, Leonard

    2016-07-01

    Cyclosporin A (CsA) is an immunosuppressant commonly used to prevent organ rejection but is associated with hyperlipidemia and an increased risk of cardiovascular disease. Although studies suggest that CsA-induced hyperlipidemia is mediated by inhibition of low-density lipoprotein receptor (LDLr)-mediated lipoprotein clearance, the data supporting this are inconclusive. We therefore sought to investigate the role of the LDLr in CsA-induced hyperlipidemia by using Ldlr-knockout mice (Ldlr(-/-)). Ldlr(-/-) and wild-type (wt) C57Bl/6 mice were treated with 20 mg/kg per d CsA for 4 weeks. On a chow diet, CsA caused marked dyslipidemia in Ldlr(-/-) but not in wt mice. Hyperlipidemia was characterized by a prominent increase in plasma very low-density lipoprotein and intermediate-density lipoprotein/LDL with unchanged plasma high-density lipoprotein levels, thus mimicking the dyslipidemic profile observed in humans. Analysis of specific lipid species by liquid chromatography-tandem mass spectrometry suggested a predominant effect of CsA on increased very low-density lipoprotein-IDL/LDL lipoprotein number rather than composition. Mechanistic studies indicated that CsA did not alter hepatic lipoprotein production but did inhibit plasma clearance and hepatic uptake of [(14)C]cholesteryl oleate and glycerol tri[(3)H]oleate-double-labeled very low-density lipoprotein-like particles. Further studies showed that CsA inhibited plasma lipoprotein lipase activity and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. We demonstrate that CsA does not cause hyperlipidemia via direct effects on the LDLr. Rather, LDLr deficiency plays an important permissive role for CsA-induced hyperlipidemia, which is associated with abnormal lipoprotein clearance, decreased lipoprotein lipase activity, and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. Enhancing LDLr and lipoprotein lipase activity and decreasing

  20. Four Statin Benefit Groups Defined by The 2013 ACC/AHA New Cholesterol Guideline are Characterized by Increased Plasma Level of Electronegative Low-Density Lipoprotein

    PubMed Central

    Chu, Chih-Sheng; Ke, Liang-Yin; Chan, Hua-Chen; Chan, Hsiu-Chua; Chen, Chih-Chieh; Cheng, Kai-Hung; Lee, Hsiang-Chun; Kuo, Hsuan-Fu; Chang, Ching-Tang; Chang, Kuan-Cheng; Sheu, Sheng-Hsiung; Chen, Chu-Huang; Lai, Wen-Ter

    2016-01-01

    Background Significantly higher cytotoxic and thrombogenic human electronegative low-density lipoprotein (LDL), or L5, has been found in patients with stable coronary artery disease and acute coronary syndrome. We hypothesized that the statin-benefit groups (SBGs) defined by the new cholesterol guideline were of higher electronegative L5. Methods In total, 62 hyperlipidemia patients (mean age 59.4 ± 10.5, M/F 40/22) were retrospectively divided into SBGs (n = 44) and N-SBGs (n = 18). The levels of complete basic lipid panel, biochemical profile and electronegative L5 of each individual were obtained before and after rosuvastatin 10 mg/day for 3 months. Results After 3 months’ statin therapy, significant reduction of total cholesterol, LDL-C and triglyceride were demonstrated (all p-values < 0.05), with 38.4% LDL-C reduction. The percentage of L5 was significantly reduced by 40.9% (from 4.4% to 2.6%) after statin therapy (p = 0.001). Regarding absolute L5 concentration, derived from L5% multiplied by LDL-C, there was approximate 63.8% reduction (from 6.3 mg/dL to 2.3 mg/dL) of absolute L5 (p < 0.001) after statin treatment. Notably, while plasma LDL-C levels were similar between SBGs and N-SBGs (152.8 ± 48.6 vs. 146.9 ± 35.0 mg/dL), the SBGs had significantly elevated L5% (5.2 ± 7.4% vs. 2.6 ± 1.9%, p = 0.031) and higher absolute L5 concentration (7.4 ± 10.4 vs. 3.7 ± 3.1 mg/dL, p = 0.036). Linear regression showed the significantly positive correlation between the plasma L5 concentration and the 10-year cardiovascular risk by pooled cohort equation (r = 0.297, p < 0.05). Conclusions The four SBGs defined by the 2013 ACC/AHA new cholesterol guideline tend to have increased atherogenic electronegative L5. Statin therapy can effectively reduce the electronegative L5 of these four major SBGs. PMID:27899853

  1. Oxidized low-density lipoprotein alters endothelial progenitor cell populations.

    PubMed

    Cui, Yuqi; Narasimhulu, Chandrakala A; Liu, Lingjuan; Li, Xin; Xiao, Yuan; Zhang, Jia; Xie, Xiaoyun; Hao, Hong; Liu, Jason Z; He, Guanglong; Cowan, Peter J; Cui, Lianqun; Zhu, Hua; Parthasarathy, Sampath; Liu, Zhenguo

    2015-06-01

    Oxidized low-density lipoprotein (ox-LDL) is critical to atherosclerosis in hyperlipidemia. Bone marrow (BM)-derived endothelial progenitor cells (EPCs) are important to preventing atherosclerosis, and significantly decreased in hyperlipidemia. This study was to demonstrate ox-LDL and hyperlipidemia could exhibit similar effect on EPC population and the role of reactive oxygen species (ROS). ROS production in BM and blood was significantly increased in male C57BL/6 mice with intravenous ox-LDL treatment, and in hyperlipidemic LDL receptor knockout mice with 4-month high-fat diet. ROS formation was effectively blocked with overexpression of antioxidant enzymes or N-acetylcysteine treatment. In hyperlipidemic and ox-LDL-treated mice, c-Kit(+)/CD31(+) cell number in BM and blood, and Sca-1(+)/Flk-1(+) cell number in blood, not in BM, were significantly decreased, which were not affected by inhibiting ROS production, while blood CD34(+)/Flk-1(+) cell number was significantly increased that was prevented with reduced ROS formation. However, blood CD34(+)/CD133(+) cell number increased in ox-LDL-treated mice, while decreased in hyperlipidemic mice. These data suggested that ox-LDL produced significant changes in BM and blood EPC populations similar (but not identical) to chronic hyperlipidemia with predominantly ROS-independent mechanism(s).

  2. Tiliroside and gnaphaliin inhibit human low density lipoprotein oxidation.

    PubMed

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

    2007-01-01

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

  3. Regulation of low-density lipoprotein subfractions by carbohydrates.

    PubMed

    Gerber, Philipp A; Berneis, Kaspar

    2012-07-01

    This article aims at reviewing the recent findings that have been made concerning the crosstalk of carbohydrate metabolism with the generation of small, dense low-density lipoprotein (LDL) particles, which are known to be associated with an adverse cardiovascular risk profile. Studies conducted during the past few years have quite unanimously shown that the quantity of carbohydrates ingested is associated with a decrease of LDL particle size and an increase in its density. Conversely, diets that aim at a reduction of carbohydrate intake are able to improve LDL quality. Furthermore, a reduction of the glycaemic index without changing the amount of carbohydrates ingested has similar effects. Diseases with altered carbohydrate metabolism, for example, type 2 diabetes, are associated with small, dense LDL particles. Finally, even the kind of monosaccharide the carbohydrate intake consists of is important concerning LDL particle size: fructose has been shown to alter the LDL particle subclass profile more adversely than glucose in many recent studies. LDL particle quality, rather than its quantity, is affected by carbohydrate metabolism, which is of clinical importance, in particular, in the light of increased carbohydrate consumption in today's world.

  4. Troglitazone inhibits long-term glycation and oxidation of low-density lipoprotein.

    PubMed

    Sobal, Grazyna; Menzel, E J; Sinzinger, H

    2005-11-01

    Troglitazone (T) is a member of a new class of antidiabetic drugs termed thiazolidinediones (TZDs), which has previously been used as an anti-diabetic agent. In this study we investigated the influence of T, a ligand for PPAR-gamma receptor, on copper-catalyzed or cell-mediated oxidation of native, glycated, and glycoxidated low-density lipoprotein (LDL). A dose-dependent inhibition of copper-mediated low-density lipoprotein-oxidation, as monitored by the formation of oxidation-specific fluorescence, was observed for both native and glycated low-density lipoprotein. At the concentration of 20 microg/mL the inhibition amounted from 14.7% to 64.7% by all low-density lipoprotein forms. For glycated low-density lipoprotein we obtained the highest oxidation rate, but the most pronounced inhibition by T was found for glycoxidated low-density lipoprotein (goLDL). Inhibitory effects of T were also investigated by measurement of relative electrophoretic mobility (REM) in the concentration range of 0 to 20 microg/mL. The inhibition of 4h oxidation of native low-density lipoprotein was found in the entire concentration range, but significance was seen at 10 microg/mL. The long-term glycation and glycoxidation of low-density lipoprotein as measured by 5-hydroxymethyl-2-furaldehyde (5-HMF) formation and binding of fructosamine was found to be inhibited by T. In endothelial cell-mediated oxidation of low-density lipoprotein cytotoxicity of T in the concentration range of 0 to 160 microg/mL during 2 to 24 h oxidation was investigated. In the non-cytotoxic concentration range of 5 to 20 microg/mL, a significantly reduced liberation of isoprostane 8-epi-PGF2alpha during 24 h cell-mediated oxidation of low-density lipoprotein and its modifications was found. This inhibitory action of T was most significant in the case of goLDL and amounted to approximately 20% to 60% inhibition at 5 to 20 microg/mL T, respectively. In the concentration range of 40 to 160 microg/mL, however, T showed

  5. Alcohol alters low density lipoprotein composition and metabolism

    SciTech Connect

    Hoinacki, J.; Brown, J.; Dawson, M.; Deschenes, R.; Mulligan, J. )

    1991-03-11

    Two separate studies were conducted to examine the effect of ethanol (EtOH) dose on atherogenic low density lipoprotein (LDL) subfractions and LDL metabolism in vivo. In the first study, male, atherosclerosis-susceptible squirrel monkeys were divided in three treatments: controls fed liquid diet, and low and high alcohol groups given liquid diet with vodka substituted for carbohydrate at 12% and 24% of calories, respectively. After 6 months, LDL subclasses (LDL{sub 1a}, LDL{sub 1b} and LDL{sub 2}) were isolated by density gradient ultracentrifugation and polyacrylamide gradient gel electrophoresis, and their lipid and protein composition was determined. Low dose EtOH had no effect on LDL subfraction distribution while 24% EtOH resulted in an increase in the larger (LDL{sub 1a} and LDL{sub 1b}), buoyant subspecies without affecting the level of the more atherogenic, smaller, denser LDL{sub 2} particles. In the second study, {sup 125}I-LDL apolipoprotein B (apo B) was injected intravenously into Control and High EtOH monkeys and kinetic analyses were performed. Although the absolute catabolic rate (LDL production) was not altered, High EtOH primates showed a reduction in the fractional catabolic rate and a longer LDL apoB residence time.

  6. Green tea catechins prevent low-density lipoprotein oxidation via their accumulation in low-density lipoprotein particles in humans.

    PubMed

    Suzuki-Sugihara, Norie; Kishimoto, Yoshimi; Saita, Emi; Taguchi, Chie; Kobayashi, Makoto; Ichitani, Masaki; Ukawa, Yuuichi; Sagesaka, Yuko M; Suzuki, Emiko; Kondo, Kazuo

    2016-01-01

    Green tea is rich in polyphenols, including catechins which have antioxidant activities and are considered to have beneficial effects on cardiovascular health. In the present study, we investigated the effects of green tea catechins on low-density lipoprotein (LDL) oxidation in vitro and in human studies to test the hypothesis that catechins are incorporated into LDL particles and exert antioxidant properties. In a randomized, placebo-controlled, double-blind, crossover trial, 19 healthy men ingested green tea extract (GTE) in the form of capsules at a dose of 1 g total catechin, of which most (>99%) was the gallated type. At 1 hour after ingestion, marked increases of the plasma concentrations of (-)-epigallocatechin gallate and (-)-epicatechin gallate were observed. Accordingly, the plasma total antioxidant capacity was increased, and the LDL oxidizability was significantly reduced by the ingestion of GTE. We found that gallated catechins were incorporated into LDL particles in nonconjugated forms after the incubation of GTE with plasma in vitro. Moreover, the catechin-incorporated LDL was highly resistant to radical-induced oxidation in vitro. An additional human study with 5 healthy women confirmed that GTE intake sufficiently increased the concentration of gallated catechins, mainly in nonconjugated forms in LDL particles, and reduced the oxidizability of LDL. In conclusion, green tea catechins are rapidly incorporated into LDL particles and play a role in reducing LDL oxidation in humans, which suggests that taking green tea catechins is effective in reducing atherosclerosis risk associated with oxidative stress.

  7. Metabolism of a Lipid Nanoemulsion Resembling Low-Density Lipoprotein in Patients with Grade III Obesity

    PubMed Central

    Dantas, Simone Alves; Ficker, Elisabeth Salvatori; Vinagre, Carmen G. C.; Ianni, Barbara Maria; Maranhão, Raul Cavalcante; Mady, Charles

    2010-01-01

    INTRODUCTION: Obesity increases triglyceride levels and decreases high-density lipoprotein concentrations in plasma. Artificial emulsions resembling lipidic plasma lipoprotein structures have been used to evaluate low-density lipoprotein metabolism. In grade III obesity, low density lipoprotein metabolism is poorly understood. OBJECTIVE: To evaluate the kinetics with which a cholesterol-rich emulsion (called a low-density emulsion) binds to low-density lipoprotein receptors in a group of patients with grade III obesity by the fractional clearance rate. METHODS: A low-density emulsion was labeled with [14C]-cholesterol ester and [3H]-triglycerides and injected intravenously into ten normolipidemic non-diabetic patients with grade III obesity [body mass index higher than 40 kg/m2] and into ten non-obese healthy controls. Blood samples were collected over 24 hours to determine the plasma decay curve and to calculate the fractional clearance rate. RESULTS: There was no difference regarding plasma levels of total cholesterol or low-density lipoprotein cholesterol between the two groups. The fractional clearance rate of triglycerides was 0.086 ± 0.044 in the obese group and 0.122 ± 0.026 in the controls (p = 0.040), and the fractional clearance rate of cholesterol ester (h−1) was 0.052 ± 0.021 in the obese subjects and 0.058 ± 0.015 (p = 0.971) in the controls. CONCLUSION: Grade III obese subjects exhibited normal low-density lipoprotein removal from plasma as tested by the nanoemulsion method, but triglyceride removal was slower. PMID:20126342

  8. Protein Kinase C-α–Mediated Regulation of Low-Density Lipoprotein Receptor–Related Protein and Urokinase Increases Astrocytoma Invasion

    PubMed Central

    Amos, Samson; Mut, Melike; diPierro, Charles G.; Carpenter, Joan E.; Xiao, Aizhen; Kohutek, Zachary A.; Redpath, Gerard T.; Zhao, Yunge; Wang, Jiahu; Shaffrey, Mark E.; Hussaini, Isa M.

    2008-01-01

    Aggressive and infiltrative invasion is one of the hallmarks of glioblastoma. Low-density lipoprotein receptor–related protein (LRP) is expressed by glioblastoma, but the role of this receptor in astrocytic tumor invasion remains poorly understood. We show that activation of protein kinase C-α (PKC-α) phosphorylated and down-regulated LRP expression. Pretreatment of tumor cells with PKC inhibitors, phosphoinositide 3-kinase (PI3K) inhibitor, PKC-α small interfering RNA (siRNA), and short hairpin RNA abrogated phorbol 12-myristate 13-acetate–induced down-regulation of LRP and inhibited astrocytic tumor invasion in vitro. In xenograft glioblastoma mouse model and in vitro transmembrane invasion assay, LRP-deficient cells, which secreted high levels of urokinase-type plasminogen activator (uPA), invaded extensively the surrounding normal brain tissue, whereas the LRP-overexpressing and uPA-deficient cells did not invade into the surrounding normal brain. siRNA, targeted against uPA in LRP-deficient clones, attenuated their invasive potential. Taken together, our results strongly suggest the involvement of PKC-α/PI3K signaling pathways in the regulation of LRP-mediated astrocytoma invasion. Thus, a strategy of combining small molecule inhibitors of PKC-α and PI3K could provide a new treatment paradigm for glioblastomas. PMID:17974965

  9. Increases in oxidized low-density lipoprotein and other inflammatory and adhesion molecules with a concomitant decrease in high-density lipoprotein in the individuals exposed to arsenic in Bangladesh.

    PubMed

    Karim, Md Rezaul; Rahman, Mashiur; Islam, Khairul; Mamun, Abdullah Al; Hossain, Shakhawoat; Hossain, Ekhtear; Aziz, Abdul; Yeasmin, Fouzia; Agarwal, Smita; Hossain, Md Imam; Saud, Zahangir Alam; Nikkon, Farjana; Hossain, Mostaque; Mandal, Abul; Jenkins, Richard O; Haris, Parvez I; Miyataka, Hideki; Himeno, Seiichiro; Hossain, Khaled

    2013-09-01

    Elevated exposure to arsenic has been suggested to be associated with atherosclerosis leading to cardiovascular disease (CVD). However, biochemical events underlying the arsenic-induced atherosclerosis have not yet been fully documented. The aim of this study was to investigate the associations of circulating molecules involved in atherosclerosis with arsenic exposure in the individuals exposed to arsenic in Bangladesh. A total of 324 study subjects, 218 from arsenic-endemic areas and 106 from nonendemic areas in Bangladesh, were recruited. Drinking water, hair, nail, and blood samples were collected from the study subjects for analysis. Total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels were lower in arsenic-endemic subjects than those of nonendemic subjects. Oxidized LDL (Ox-LDL), C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) levels were significantly higher in arsenic-endemic subjects than those in nonendemic subjects. All these circulating molecules showed significant correlations with arsenic exposure (water, hair, and nail arsenic concentrations), and all these relations were significant before and after adjusting for relevant covariates. Among the circulating molecules tested in this study, HDL, Ox-LDL, and CRP showed dose-response relationships with arsenic exposure. Ox-LDL/HDL ratios were increased with the increasing concentrations of arsenic in the water, hair, and nails. Furthermore, non-HDL cholesterol and TC/HDL ratios were significantly correlated with arsenic exposure before and after adjusting for relevant covariates. Thus, all the observed associations may be the major features of arsenic exposure-related atherosclerosis leading to CVD.

  10. Oxidized low-density lipoprotein induces hematopoietic stem cell senescence.

    PubMed

    Zhang, Xian-Ping; Zhang, Gui-Hai; Wang, Yu-Ying; Liu, Jun; Wei, Qiang; Xu, Chun-Yan; Wang, Jian-Wei; Wang, Ya-Ping

    2013-09-01

    We have investigated oxidized low-density lipoprotein (ox-LDL) induced senescence in hematopoietic stem cells (HCs). Mouse Sca-1+ HCs were separated and purified using the magnetic activated cell sorting technique. Ox-LDL induced significant senescence in HCs measured by SA-β-Gal staining, and reduced CFU-Mix colony-forming capacity, arresting cells at G0/G1 phase. In agreement with the cell cycle arrest, ox-LDL markedly reduced the expression of CDK4, cyclin D, and cyclin E. As possible contributing factors for cell senescence, ox-LDL also induced cellular oxidative stress and reduced telomerase activity.

  11. Low density lipoprotein and very low density lipoprotein are selectively bound by aggregated C-reactive protein.

    PubMed

    de Beer, F C; Soutar, A K; Baltz, M L; Trayner, I M; Feinstein, A; Pepys, M B

    1982-07-01

    C-reactive protein (CRP), the classical acute-phase protein, can bind phospholipids by virtue of its specific, calcium-dependent reactivity with phosphorylcholine residues. However, analysis of acute-phase serum by gel filtration and by density gradient ultracentrifugation showed that the CRP was in a free, uncomplexed form, despite the coexistent presence of the various classes of serum lipoproteins, all of which contain phospholipids. In contrast, when isolated CRP was aggregated by immobilization at a sufficient density on a solid phase and then exposed to normal human serum, it selectively bound low density lipoprotein (LDL) and traces of very low density lipoprotein. The reaction was calcium dependent and reversible by free phosphorylcholine but not by heparin. LDL isolated from normal plasma was also bound by aggregated CRP. CRP reacts in vitro with a wide variety of different ligands both of extrinsic and of autogenous origin, e.g., microbial products and damaged cell membranes, respectively. If CRP aggregated in vivo by complexing with these ligands than acquires the capacity to selectively bind LDL, the phenomenon may have significant implications for the function of CRP and for the metabolism, clearance, and deposition of LDL.

  12. Familial defective apolipoprotein B-100 and increased low-density lipoprotein cholesterol and coronary artery calcification in the old order amish.

    PubMed

    Shen, Haiqing; Damcott, Coleen M; Rampersaud, Evadnie; Pollin, Toni I; Horenstein, Richard B; McArdle, Patrick F; Peyser, Patricia A; Bielak, Lawrence F; Post, Wendy S; Chang, Yen-Pei C; Ryan, Kathleen A; Miller, Michael; Rumberger, John A; Sheedy, Patrick F; Shelton, John; O'Connell, Jeffrey R; Shuldiner, Alan R; Mitchell, Braxton D

    2010-11-08

    Elevated low-density lipoprotein cholesterol (LDL-C) levels are a major cardiovascular disease risk factor. Genetic factors are an important determinant of LDL-C levels. To identify single nucleotide polymorphisms associated with LDL-C and subclinical coronary atherosclerosis, we performed a genome-wide association study of LDL-C in 841 asymptomatic Amish individuals aged 20 to 80 years, with replication in a second sample of 663 Amish individuals. We also performed scanning for coronary artery calcification (CAC) in 1018 of these individuals. From the initial genome-wide association study, a cluster of single nucleotide polymorphisms in the region of the apolipoprotein B-100 gene (APOB) was strongly associated with LDL-C levels (P < 10(-68)). Additional genotyping revealed the presence of R3500Q, the mutation responsible for familial defective apolipoprotein B-100, which was also strongly associated with LDL-C in the replication sample (P < 10(-36)). The R3500Q carrier frequency, previously reported to be 0.1% to 0.4% in white European individuals, was 12% in the combined sample of 1504 Amish participants, consistent with a founder effect. The mutation was also strongly associated with CAC in both samples (P < 10(-6) in both) and accounted for 26% and 7% of the variation in LDL-C levels and CAC, respectively. Compared with noncarriers, R3500Q carriers on average had LDL-C levels 58 mg/dL higher, a 4.41-fold higher odds (95% confidence interval, 2.69-7.21) of having detectable CAC, and a 9.28-fold higher odds (2.93-29.35) of having extensive CAC (CAC score ≥400). The R3500Q mutation in APOB is a major determinant of LDL-C levels and CAC in the Amish.

  13. Increase in the oxidised low-density lipoprotein level by smoking and the possible inhibitory effect of statin therapy in patients with cardiovascular disease: a retrospective study

    PubMed Central

    Ogawa, Kazuo; Tanaka, Toshikazu; Nagoshi, Tomohisa; Sekiyama, Hiroshi; Arase, Satoshi; Minai, Kosuke; Ogawa, Takayuki; Yoshimura, Michihiro

    2015-01-01

    Objectives Malondialdehyde-modified low-density lipoprotein (MDA-LDL) level is a marker of oxidative stress and is linked to progression of arteriosclerosis; however, the clinical factors affecting the oxidised LDL level have not been elucidated. We investigate various factors to identify correlation with MDA-LDL level in high-risk patients requiring catheter intervention. Setting Secondary care (cardiology), single-centre study. Participants 600 patients who were admitted to our hospital and underwent cardiac catheterisation. Primary and secondary outcome measures Blood samples were obtained to measure lipid profiles and MDA-LDL level. Results With regard to smoking status, MDA-LDL level was significantly higher in ex-smokers/current smokers compared with non-smokers. Of note, there was no improvement of MDA-LDL level even in patients who had quit smoking. Multiple regression analysis showed that MDA-LDL level was positively correlated with LDL-cholesterol (LDL-C) level, Brinkman index and male gender. The correlation between smoking status and either MDA-LDL or LDL-C level was investigated in two groups: namely, patients with and patients without statin treatment. In the non-statin group, MDA-LDL level and MDA-LDL/LDL-C ratio were significantly higher in ex-smokers/current smokers compared with non-smokers, while no significant correlation was observed between smoking status and LDL-C level. In contrast, in the statin group, there were no significant correlations between smoking status and any of the cholesterol parameters. Conclusions We found that MDA-LDL level was affected by multiple factors, such as smoking status, LDL-C level and male gender. The present findings give additional evidence that smoking should be prohibited from a MDA-LDL standpoint. Furthermore, statin therapy might have a beneficial effect on the reduction of MDA-LDL level. PMID:25609666

  14. Aggregation and fusion of modified low density lipoprotein.

    PubMed

    Pentikäinen, M O; Lehtonen, E M; Kovanen, P T

    1996-12-01

    In atherogenesis, low density lipoprotein (LDL, diameter 22 nm) accumulates in the extracellular space of the arterial intima in the form of aggregates of lipid droplets (droplet diameter up to 400 nm). Here we studied the effects of various established in vitro LDL modifications on LDL aggregation and fusion. LDL was subjected to vortexing, oxidation by copper ions, proteolysis by alpha-chymotrypsin, lipolysis by sphingomyelinase, and nonenzymatic glycosylation, and was induced to form adducts with malondialdehyde or complexes with anti-apoB-100 antibodies. To assess the amount of enlarged LDL-derived structures formed (due to aggregation or fusion), we measured the turbidity of solutions containing modified LDL, and quantified the proportion of modified LDL that 1) sedimented at low-speed centrifugation (14,000 g), 2) floated at an increased rate at high-speed centrifugation (rate zonal flotation at 285,000 gmax), 3) were excluded in size-exclusion column chromatography (exclusion limit 40 MDa), or 4) failed to enter into 0.5%. Fast Lane agarose gel during electrophoresis. To detect whether particle fusion had contributed to the formation of the enlarged LDL-derived structures, particle morphology was examined using negative staining and thin-section transmission electron microscopy. We found that 1) aggregation was induced by the formation of LDL-antibody complexes, malondialdehyde treatment, and glycosylation of LDL; 2) fusion of LDL was induced by proteolysis of LDL by alpha-chymotrypsin; and 3) aggregation and fusion of LDL were induced by vortexing, oxidation by copper ions, and lipolysis by sphingomyclinase of LDL. The various modifications of LDL differed in their ability to induce aggregation and fusion.

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

    PubMed Central

    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

    2015-01-01

    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

  16. Low-density lipoprotein receptor-related protein-1 facilitates heme scavenging after intracerebral hemorrhage in mice.

    PubMed

    Wang, Gaiqing; Manaenko, Anatol; Shao, Anwen; Ou, Yibo; Yang, Peng; Budbazar, Enkhjargal; Nowrangi, Derek; Zhang, John H; Tang, Jiping

    2017-04-01

    Heme-degradation after erythrocyte lysis plays an important role in the pathophysiology of intracerebral hemorrhage. Low-density lipoprotein receptor-related protein-1 is a receptor expressed predominately at the neurovascular interface, which facilitates the clearance of the hemopexin and heme complex. In the present study, we investigated the role of low-density lipoprotein receptor-related protein-1 in heme removal and neuroprotection in a mouse model of intracerebral hemorrhage. Endogenous low-density lipoprotein receptor-related protein-1 and hemopexin were increased in ipsilateral brain after intracerebral hemorrhage, accompanied by increased hemoglobin levels, brain water content, blood-brain barrier permeability and neurological deficits. Exogenous human recombinant low-density lipoprotein receptor-related protein-1 protein reduced hematoma volume, brain water content surrounding hematoma, blood-brain barrier permeability and improved neurological function three days after intracerebral hemorrhage. The expression of malondialdehyde, fluoro-Jade C positive cells and cleaved caspase 3 was increased three days after intracerebral hemorrhage in the ipsilateral brain tissues and decreased with recombinant low-density lipoprotein receptor-related protein-1. Intracerebral hemorrhage decreased and recombinant low-density lipoprotein receptor-related protein-1 increased the levels of superoxide dismutase 1. Low-density lipoprotein receptor-related protein-1 siRNA reduced the effect of human recombinant low-density lipoprotein receptor-related protein-1 on all outcomes measured. Collectively, our findings suggest that low-density lipoprotein receptor-related protein-1 contributed to heme clearance and blood-brain barrier protection after intracerebral hemorrhage. The use of low-density lipoprotein receptor-related protein-1 as supplement provides a novel approach to ameliorating intracerebral hemorrhage brain injury via its pleiotropic neuroprotective effects.

  17. Oxidized low-density lipoprotein in postmenopausal women.

    PubMed

    Kork, Felix; Jankowski, Vera; Just, Alexander R; Pfeilschifter, Johannes; Tepel, Martin; Zidek, Walter; Jankowski, Joachim

    2014-07-01

    Oxidized low-density lipoprotein (oxLDL) leads to atherosclerosis and cardiovascular disease, the most frequent causes of death worldwide. After menopause, lipid and lipoprotein metabolism changes and women are at greater risk of cardiovascular disease compared to fertile women. The aim of this study was to determine the prevalence of serum oxLDL in postmenopausal women and to identify possible associations of clinical and laboratory features with oxLDL in these patients. After clinical examination and completing a clinical questionnaire, an ultrasound examination of both carotid arteries was conducted and blood was drawn from 533 postmenopausal women. oxLDL concentration was determined using proton NMR spectroscopy. Oxidized LDL was detected in 12.4% (95% confidence interval 9.7-15.5) of postmenopausal women with a median of 0.18 mg/dl (interquartile range 0.10-0.43). Although intima-media thickness did not differ, postmenopausal women with serous oxLDL had more often atherosclerotic plaques compared to women without oxLDL (6/66 vs. 0/467; P < 0.01). Higher concentrations of high-density lipoprotein, impaired glucose intolerance, and DBP were independently associated with the occurrence of oxLDL. If oxLDL was present, higher high-density lipoprotein and glucose intolerance were associated with higher concentrations of oxLDL. In contrast, higher blood urea concentrations were associated with lower concentrations of oxLDL. This study presents the prevalence and concentration of oxLDL in postmenopausal women and demonstrates that oxLDL concentration can be quantified by proton NMR spectroscopy in large patient samples. The data suggest that oxLDL may be a biomarker for incipient atherosclerotic changes in postmenopausal women. In contrary to the association of dyslipoproteinemia and diabetes, higher blood urea concentrations were associated with lower concentrations of oxLDL.

  18. Cryoelectron microscopy of low density lipoprotein in vitreous ice.

    PubMed Central

    Spin, J M; Atkinson, D

    1995-01-01

    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

  19. Human very low density lipoproteins and chylomicrons can protect against endotoxin-induced death in mice.

    PubMed Central

    Harris, H W; Grunfeld, C; Feingold, K R; Rapp, J H

    1990-01-01

    Endotoxemia stimulates many physiologic responses including disturbances in lipid metabolism. We hypothesized that this lipemia may be part of a defensive mechanism by which the body combats the toxic effects of circulating endotoxin. We tested the effects of mixtures of endotoxin, lipoproteins, and lipoprotein-free plasma and determined the ability of varying concentrations of human very low density lipoproteins (VLDL) and chylomicrons, as well as low density lipoproteins (LDL) and high density lipoproteins (HDL), and of the synthetic lipid emulsion SOYACAL to prevent endotoxin-induced death in mice. This study demonstrates that the triglyceride-rich VLDL and chylomicrons, as well as cholesterol-rich LDL and HDL, and cholesterol-free SOYACAL can protect against endotoxin-induced death. Protection required small amounts of lipoprotein-free plasma, and depended on the incubation time and the concentration of lipoprotein lipid. Despite stringent techniques to prevent exogenous endotoxin contamination eight of ten duplicate VLDL preparations contained endotoxin (5,755 +/- 3,514 ng endotoxin/mg triglyceride, mean +/- SEM) making the isolation of endotoxin-free VLDL difficult. In contrast, simultaneous preparations of LDL and HDL were relatively free of endotoxin contamination (3 +/- 3 and 320 +/- 319 ng/mg total cholesterol, respectively), suggesting that the contamination of VLDL occurs in vivo and not during the isolation procedure. These observations suggest a possible role for increased triglyceride-rich lipoproteins in the host's defense against endotoxemia and infection. Images PMID:2394827

  20. The mushroom Pleurotus ostreatus accelerates plasma very-low-density lipoprotein clearance in hypercholesterolemic rat.

    PubMed

    Bobek, P; Ozdín, L

    1994-01-01

    The administration of a diet containing 5% of dried oyster mushroom to male Wistar rats fed a cholesterol diet (0.3%) shortly after weaning for 8 weeks reduced cholesterol levels in the serum and liver by 27 and 33%, respectively and increased the fractional turnover rate of 125I-very-low-density lipoproteins (VLDL) by more than 30%.

  1. Chylomicron remnant cholesteryl esters as the major constituent of very low density lipoproteins in plasma of cholesterol-fed rabbits.

    PubMed

    Ross, A C; Zilversmit, D B

    1977-03-01

    Feeding rabbits 500 mg of cholesterol daily for 4 to 15 days greatly increased the concentration of esterified cholesterol in lipoproteins of d less than 1.006 g/ml. The origin of hypercholesterolemic very low density lipoproteins was investigated by monitoring the degradation of labeled lymph chyomicrons administered to normal and cholesterol-fed rabbits. Chylomicrons were labeled in vivo by feeding either 1) [3H]cholesterol and [14C]oleic acid or 2) [14C]cholesterol and [3H]retinyl acetate. After intravenous injection of labeled chylomicrons to recipient rabbits, [14C]triglyceride hydrolysis was equally rapid in normal and cholesterol-fed animals. Normal rabbits rapidly removed from plasma both labeled cholesteryl and retinyl esters, whereas cholesterol-fed rabbits retained nearly 50% of doubly labeled remnants in plasma 25 min after chylomicron injection. Ultracentrifugal separation of plasma into subfractions of very low density lipoproteins showed that chylomicron remnants in cholesterol-fed animals are found among all subclasses of very low density lipoproteins. Analysis of cholesteryl ester specific activity-time curves for the very low density lipoproteins subfraction from hypercholesterolemic plasma showed that nearly all esterified cholesterol in large very low density lipoproteins and approximately 30% of esterified cholesterol in small very low density lipoproteins was derived from chylomicron degradation. Apparently, nearly two-thirds of the esterified cholesterol in total very low density lipoproteins from moderately hypercholesterolemic rabbits is of dietary origin.

  2. Increased serum soluble lectin-like oxidized low-density lipoprotein receptor-1 levels in patients with biopsy-proven nonalcoholic fatty liver disease

    PubMed Central

    Ozturk, Oguzhan; Colak, Yasar; Senates, Ebubekir; Yilmaz, Yusuf; Ulasoglu, Celal; Doganay, Levent; Ozkanli, Seyma; Oltulu, Yasemin Musteri; Coskunpinar, Ender; Tuncer, Ilyas

    2015-01-01

    AIM: To analyze the relationship between the serum lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) levels and clinical and histopathological features of biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) patients. METHODS: Fifty-three consecutive, biopsy-proven NAFLD patients (31 males and 22 females, mean age 42.5 ± 9.6 years) and 26 age- and gender-matched, healthy controls (14 males and 12 females, mean age 39 ± 10.7 years) were included. The patients with NAFLD were consecutive patients who had been admitted to the hepatology outpatient clinic within the last year and had been diagnosed with NAFLD as the result of liver biopsy. The healthy controls were individuals who attended the outpatient clinic for routine health control and had no known chronic illnesses. The histological evaluation was conducted according to the NAFLD activity scoring system recommended by The National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. The serum LOX-1 levels were measured using an ELISA kit (Life Science Inc. USCN. Wuhan, Catalog No. E1859Hu) in both patients and healthy controls. A receiver operating characteristic (ROC) curve analysis was used to identify the optimal cutoff value of LOX-1 and thereby distinguish between patients with nonalcoholic steatohepatitis (NASH) and healthy controls. A P-value < 0.05 was considered statistically significant. RESULTS: NAFLD and healthy control groups were similar in terms of age and sex. NAFLD patients consisted of 8 patients with simple steatosis (15%), 27 with borderline NASH (51%) and 18 with definitive NASH (34%). Metabolic syndrome was found in 62.2% of the patients with NAFLD. The mean serum LOX-1 level in biopsy-proven NAFLD patients was 8.49 ± 6.43 ng/mL compared to 4.08 ± 4.32 ng/mL in healthy controls (P = 0.001). The LOX-1 levels were significantly different between controls, simple steatosis and NASH (borderline+definite) cases (4

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

    SciTech Connect

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

    1987-01-01

    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.

  4. New roles of low density lipoproteins and vitamin E in the pathogenesis of atherosclerosis.

    PubMed

    Ozer, N K; Boscoboinik, D; Azzi, A

    1995-01-01

    Accumulation of oxidized low density lipoproteins in macrophages and smooth muscle cells causes foam cell formation, an initial step in atherosclerosis. Active oxygen species are considered important in the pathogenesis of the disease. Antioxidants, such as tocopherols and tocotrienols have been considered to prevent the deleterious effects of active oxygen species. We found native low density lipoproteins can stimulate directly smooth muscle cell proliferation, it is associated with an increase of protein kinase C activity. d-alpha-Tocopherol, biologically most active form of vitamin E, inhibits both cell proliferation and protein kinase C activity. The effect of d-alpha-tocopherol is not related to its radical scavenging properties. Transforming growth factor-beta secreted by smooth muscle cells as growth inhibitor. Low density lipoproteins decrease the release of transforming growth factor-beta from smooth muscle cells thus activating growth. d-alpha-Tocopherol activates the cellular release of transforming growth factor-beta. These new aspects explain the important role of low density lipoproteins and vitamin E in increasing and decreasing the risk of atherosclerosis, respectively.

  5. Cost Effectiveness of Achieving Targets of Low-Density Lipoprotein Particle Number Versus Low-Density Lipoprotein Cholesterol Level.

    PubMed

    Grabner, Michael; Winegar, Deborah A; Punekar, Rajeshwari S; Quimbo, Ralph A; Cziraky, Mark J; Cromwell, William C

    2017-02-01

    A recent analysis of a commercially insured US population found fewer cardiovascular disease (CVD) events in high-risk patients attaining low levels of low-density lipoprotein (LDL), as measured by LDL particle number (LDL-P) versus low LDL cholesterol (LDL-C). Here, we investigated the cost effectiveness of LDL-lowering therapy guided by LDL-P. Patients were selected from the HealthCore Integrated Research Database and followed for 12 to 36 months. Patients who achieved LDL-P <1,000 nmol/l were placed into the LDL-P cohort, whereas those without LDL-P tests, but who achieved LDL-C <100 mg/dl, were placed into the LDL-C cohort. CVD-related costs included all health plan paid amounts related to CVD events or lipid management. Cost effectiveness was assessed through incremental cost-effectiveness ratios, defined as difference in total costs across the cohorts divided by difference in CVD events, measured over follow-up. Each cohort included 2,094, 1,242, and 705 patients over 12-, 24-, and 36-month follow-up. Patients in the LDL-P cohort received more aggressive lipid-lowering therapy and had fewer CVD events during follow-up compared to patients in the LDL-C cohort. This led to greater pharmacy costs and lower medical costs over time. Incremental cost-effectiveness ratio estimates ranged from $23,131 per CVD event avoided at 12 months to $3,439 and -$4,555 at 24- and 36-month follow-up, suggesting a high likelihood that achieving LDL-P <1,000 nmol/l is cost effective. In conclusion, LDL-lowering therapy guided by LDL-P was demonstrated to be cost effective, with greater clinical and economic benefit seen over longer time horizons and with the increased use of generic statins. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  6. Thermal transitions in the low-density lipoprotein and lipids of the egg yolk of hens.

    PubMed

    Smith, M B; Back, J F

    1975-05-22

    1. Differential sanning calorimetry and light-scattering have been used to investigate temperature-dependent transitions in low-density lipoprotein and in lipids from hens' egg yolk. Yolks of different fatty acid composition were obtained by varying the dietary lipid and by adding methyl sterculate to the hen's diet. 2. Lipoprotein solutions in 50 percent glycerol/water gave characteristic melting curves between -25 degrees C and 50 degrees C, and on cooling showed increases in light-scattering between 10 degrees C and -20 degrees C. The temperatures at which major changes occurred depended on the proportions of saturated and unsaturated fatty acids. 3. The thermal transitions in the intact lipoprotein in glycerol solution were reversible, but with marked hysteresis. Lipid extracted from the lipoprotein did not show temperature hystersis but the transition heats and melting curves similar to those of the intact lipoprotein. The results support the hypothesis of a "lipid-core" structure for low-density lipoproteins. 4. Scanning calorimetry of egg-yolk lecithins indicated a strong dependence of transition temperature on water content in the rane 3 percent-20 percent water. A rise in the mid-temperature of the liquid-crystalline to gel transition as the water content is lowered on freezing may be the primary event in the irreversible gelation of egg yolk and aggregation of lipoprotein.

  7. Krill oil supplementation lowers serum triglycerides without increasing low-density lipoprotein cholesterol in adults with borderline high or high triglyceride levels.

    PubMed

    Berge, Kjetil; Musa-Veloso, Kathy; Harwood, Melody; Hoem, Nils; Burri, Lena

    2014-02-01

    The aim of the study was to explore the effects of 12 weeks daily krill oil supplementation on fasting serum triglyceride (TG) and lipoprotein particle levels in subjects whose habitual fish intake is low and who have borderline high or high fasting serum TG levels (150-499 mg/dL). We hypothesized that Krill oil lowers serum TG levels in subjects with borderline high or high fasting TG levels. To test our hypothesis 300 male and female subjects were included in a double-blind, randomized, multi-center, placebo-controlled study with five treatment groups: placebo (olive oil) or 0.5, 1, 2, or 4 g/day of krill oil. Serum lipids were measured after an overnight fast at baseline, 6 and 12 weeks. Due to a high intra-individual variability in TG levels, data from all subjects in the four krill oil groups were pooled to increase statistical power, and a general time- and dose-independent one-way analysis of variance was performed to assess efficacy. Relative to subjects in the placebo group, those administered krill oil had a statistically significant calculated reduction in serum TG levels of 10.2%. Moreover, LDL-C levels were not increased in the krill oil groups relative to the placebo group. The outcome of the pooled analysis suggests that krill oil is effective in reducing a cardiovascular risk factor. However, owing to the individual fluctuations of TG concentrations measured, a study with more individual measurements per treatment group is needed to increase the confidence of these findings. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Phospholipase D-modified low density lipoprotein is taken up by macrophages at increased rate. A possible role for phosphatidic acid.

    PubMed Central

    Aviram, M; Maor, I

    1993-01-01

    Macrophage uptake of modified forms of LDL leads to cellular cholesterol accumulation. Upon incubation of LDL with phospholipase D (PLase D), a time- and enzyme dose-dependent production of phosphatidic acid (PA), paralleled by a rapid reduction in LDL phosphatidyl choline content (up to 65% within 15 min of incubation) was noted. No lipid peroxidation could be found in PLase D-modified LDL. Upon in vitro incubation of PLase D-LDL with copper ions, however, this modified LDL was substantially oxidized. The addition of 100 micrograms PA/ml to native LDL for the period of its in vitro oxidation resulted in a 63% elevation in the lipoprotein peroxides content. Incubation of PLase D-LDL with J-774A.1 macrophage-like cell line resulted in an increase in its cellular binding and degradation (up to 91 and 110%, respectively) in comparison with native LDL (via the LDL receptor). When PA was added to LDL before its incubation with the macrophages, a PA dose-dependent elevation in the cellular uptake of LDL (by up to twofold) was noted in comparison with LDL that was incubated without PA, suggesting that PA production in PLase D-LDL may be involved in the increased cellular uptake of PLase D-LDL. PLase D activity towards LDL was demonstrated in J-774A.1 macrophages. Human plasma was also shown to possess PLase D activity. Thus, PLase D modification of LDL may take place under certain pathological conditions and PLase D-LDL interaction with arterial wall macrophages can potentially lead to foam cell formation. PMID:8486764

  9. Constitutive androstane receptor activation decreases plasma apolipoprotein B-containing lipoproteins and atherosclerosis in low-density lipoprotein receptor-deficient mice.

    PubMed

    Sberna, Anne-Laure; Assem, Mahfoud; Xiao, Rui; Ayers, Steve; Gautier, Thomas; Guiu, Boris; Deckert, Valérie; Chevriaux, Angélique; Grober, Jacques; Le Guern, Naig; Pais de Barros, Jean-Paul; Moore, David D; Lagrost, Laurent; Masson, David

    2011-10-01

    The goal of this study was to determine the impact of the nuclear receptor constitutive androstane receptor (CAR) on lipoprotein metabolism and atherosclerosis in hyperlipidemic mice. Low-density lipoprotein receptor-deficient (Ldlr(-/-)) and apolipoprotein E-deficient (ApoE(-/-)) mice fed a Western-type diet were treated weekly with the Car agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or the vehicle only for 8 weeks. In Ldlr(-/-) mice, treatment with TCPOBOP induced a decrease in plasma triglyceride and intermediate-density lipoprotein/low-density lipoprotein cholesterol levels (≈30% decrease in both cases after 2 months, P<0.01). These mice also showed a significant reduction in the production of very-low-density lipoproteins associated with a decrease in hepatic triglyceride content and the repression of several genes involved in lipogenesis. TCPOBOP treatment also induced a marked increase in the very-low-density lipoprotein receptor in the liver, which probably contributed to the decrease in intermediate-density lipoprotein/low-density lipoprotein levels. Atherosclerotic lesions in the aortic valves of TCPOBOP-treated Ldlr(-/-) mice were also reduced (-60%, P<0.001). In ApoE(-/-) mice, which lack the physiological apoE ligand for the very-low-density lipoprotein receptor, the effect of TCPOBOP on plasma cholesterol levels and the development of atherosclerotic lesions was markedly attenuated. CAR is a potential target in the prevention and treatment of hypercholesterolemia and atherosclerosis.

  10. Nonpharmacological approaches for reducing serum low-density lipoprotein cholesterol.

    PubMed

    Griffin, Bruce A

    2014-07-01

    To reinforce the key role of diet and lifestyle modification as the first-line treatment for the reduction of raised serum low-density lipoprotein cholesterol (LDL-C) and prevention of cardiovascular disease. Also, to counter recent claims that the current dietary guidelines for the treatment of cardiovascular disease have misplaced emphasis on the importance of removing dietary saturated fat instead of sugar. This review provides new insight into the effects of diet and lifestyle factors with established efficacy in lowering serum LDL-C. This includes energy-restricted weight loss and new findings on the effects of alternative day fasting; novel metabolic and molecular effects of replacing palmitic acid with oleic acid; evidence for a dose-response relationship between the intake of dietary stanols and LDL-C; and identification of a unique metabolic pathway for the excretion of cholesterol. The review reports new evidence for the efficacy of alternate day fasting, reassurance that the current dietary guidelines are not misguided by recommending removal of saturated fat, that a high intake of dietary stanols can achieve a reduction in LDL-C of up to 18%, and describes a pathway of cholesterol excretion that may help to explain variation in the response of serum LDL-C to dietary fat and cholesterol.

  11. Fast protein chromatofocusing of human very-low-density lipoproteins.

    PubMed

    Weisweiler, P; Friedl, C; Schwandt, P

    1986-01-03

    Using fast protein chromatofocusing, a high-efficiency column chromatography method with a self-generated pH gradient and focusing effects, soluble human very-low-density lipoprotein (VLDL) apolipoproteins were fractionated between pH 6.3 and 4.0. In the presence of 6 mol/l urea and with a flow rate of 1 ml/min, one run (up to 10 mg of protein) took 30 min. VLDL apolipoproteins were separated in seven peaks. As revealed by SDS-polyacrylamide gel electrophoresis, isoelectric focusing and double-immunodiffusion against mono-specific antisera, fractions corresponded to the following proteins: apolipoprotein C-I, albumin, apolipoproteins A-I, E, C-II plus C-III0, C-III1 and C-III2, respectively. Apolipoproteins were eluted in sharp, well-resolved peaks. The recovery of proteins was 78% of the starting material. With fast protein chromatofocusing, an efficient isolation of single apolipoproteins is possible from small amounts of VLDL apolipoprotein preparations. This technique is superior to the commonly used, time-consuming methods for apolipoprotein isolation.

  12. Native low density lipoprotein promotes lipid raft formation in macrophages

    PubMed Central

    SONG, JIAN; PING, LING-YAN; DUONG, DUC M.; GAO, XIAO-YAN; HE, CHUN-YAN; WEI, LEI; WU, JUN-ZHU

    2016-01-01

    Oxidized low-density lipoprotein (LDL) has an important role in atherogenesis; however, the mechanisms underlying cell-mediated LDL oxidation remain to be elucidated. The present study investigated whether native-LDL induced lipid raft formation, in order to gain further insight into LDL oxidation. Confocal microscopic analysis revealed that lipid rafts were aggregated or clustered in the membrane, which were colocalized with myeloperoxidase (MPO) upon native LDL stimulation; however, in the presence of methyl-β-cyclodextrin (MβCD), LDL-stimulated aggregation, translocation, and colocalization of lipid rafts components was abolished.. In addition, lipid raft disruptors MβCD and filipin decreased malondialdehyde expression levels. Density gradient centrifugation coupled to label-free quantitative proteomic analysis identified 1,449 individual proteins, of which 203 were significantly upregulated following native-LDL stimulation. Functional classification of the proteins identified in the lipid rafts revealed that the expression levels of translocation proteins were upregulated. In conclusion, the results of the present study indicated that native-LDL induced lipid raft clustering in macrophages, and the expression levels of several proteins were altered in the stimulated macrophages, which provided novel insights into the mechanism underlying LDL oxidation. PMID:26781977

  13. Low-density-lipoprotein receptors in different rabbit liver cells.

    PubMed Central

    Nenseter, M S; Myklebost, O; Blomhoff, R; Drevon, C A; Nilsson, A; Norum, K R; Berg, T

    1989-01-01

    Receptor-dependent uptake mechanisms for low-density lipoprotein (LDL) were studied in rabbit liver parenchymal and non-parenchymal cells. Hybridization studies with a cDNA probe revealed that mRNA for the apo (apolipoprotein) B,E receptor was present in endothelial and Kupffer cells as well as in parenchymal cells. By ligand-blotting experiments we showed that apo B,E-receptor protein was present in both parenchymal and non-parenchymal cells. Studies of binding of homologous LDL in cultured rabbit parenchymal cells suggested that about 63% of the specific LDL binding was mediated via the apo B,E receptor. Approx. 47% of the specific LDL binding was dependent on Ca2+, suggesting that specific Ca2+-dependent as well as Ca2+-independent LDL-binding sites exist in liver parenchymal cells. Methylated LDL bound to the parenchymal cells in a saturable manner. Taken together, our results showed that apo B,E receptors are present in rabbit liver endothelial and Kupffer cells as well as in the parenchymal cells, and that an additional saturable binding activity for LDL may exist on rabbit liver parenchymal cells. This binding activity was not inhibited by EGTA or reductive methylation of lysine residues in apo B. LDL degradation in parenchymal cells was mainly mediated via the apo B,E receptor. Images Fig. 1. Fig. 2. PMID:2549976

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

    SciTech Connect

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

    1981-01-01

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

  15. Development of an integrated model for analysis of the kinetics of apolipoprotein B in plasma very low density lipoproteins, intermediate density lipoproteins, and low density lipoproteins.

    PubMed Central

    Beltz, W F; Kesäniemi, Y A; Howard, B V; Grundy, S M

    1985-01-01

    To quantify more precisely the metabolism of apolipoprotein B (apo B) in human beings, an integrated model was developed for the analysis of the isotope kinetics of apo B in very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins (LDL). The experimental basis for model development was a series of 30 triple-isotope studies in which patients received autologous 131I-VLDL, 125I-IDL, and [3H]glycerol as a precursor of VLDL triglycerides. The currently proposed model contains the following components: (a) a VLDL delipidation cascade that has a variable number of subcompartments, (b) a slowly catabolized pool of VLDL, (c) an IDL compartment consisting of two closely connected subcompartments, one of which is outside the immediate circulation, and (d) a two-compartment subsystem for LDL. Because mass data indicate that not all VLDL were converted to LDL, the model allows for irreversible removal of apo B from VLDL (or IDL) subsystems. It accounts for apparent "direct" input of LDL by postulating an early, rapidly metabolized compartment of VLDL that is converted directly to IDL. The model appears to be consistent with specific activity curves from the current triple-isotope studies and with present concepts of lipoprotein physiology; it also can be used to quantify pathways of lipoprotein apo B transport in normal and abnormal states. PMID:4031063

  16. [The high content of palmitinic fatty acid in food as a major cause of increase of concentration of cholesterol and low density lipoproteins and atheromatous plaques of arteries' intima].

    PubMed

    Titov, V N

    2013-02-01

    The positioning of individual triglycerides of blood serum in palmitinic and oleic lipoproteins ofvery low density in the order ofincrease of the rate constant of their hydrolysis under action of post-heparin lipoprotein leads to the sequence as follows: palmitoil-palmitoil-palmitate-->palmitoil-palmitoil-oleate-->palmitoil-oleil-palmitat-->oleil-palmitoil-palmitate-->oleil-palmitate-palmitate-->oleil-oleil-palmitate-->oleil-oleil-oleate. The shift to the left and to the right is discerned with this spectrum of isoforms of triglycerides. The shift to the left into direction of palmitinicc triglycerides occurs in case of eating of animal food (i.e. beef andfoodstuf of fat saw milk) when the content of palmitinic saturated fatty acid supersedes 15% of fatty acids total and under the development of endogenic syndrome of insulin resistance. The content of low density lipoproteins cholesterol is high in blood The shift to the right with prevalence of oleinic triglycerides occurs in case of low content of beef and foodstuff of fat saw milk in food, fish eating, seafood and olive oil. The physiologic levels of carbohydrates in food and insulin function are present too. The shift to the right initiates the action of insulin, ometa-3 essential polyenic fatty acids, glytazones and fibrates. They increase the activity of delta9-stearil-KoA-desaturase-2 and the transformation of palmitine saturated fatty acid into mono unsaturated oleinic fatty acid. The shift to the left forms the palmitine alternative of metabolism of substrate to supply cells with energy. The shift to the right is a more effective oleinic alternative.

  17. Social Inclusion Predicts Lower Blood Glucose and Low-Density Lipoproteins in Healthy Adults.

    PubMed

    Floyd, Kory; Veksler, Alice E; McEwan, Bree; Hesse, Colin; Boren, Justin P; Dinsmore, Dana R; Pavlich, Corey A

    2016-07-27

    Loneliness has been shown to have direct effects on one's personal well-being. Specifically, a greater feeling of loneliness is associated with negative mental health outcomes, negative health behaviors, and an increased likelihood of premature mortality. Using the neuroendocrine hypothesis, we expected social inclusion to predict decreases in both blood glucose levels and low-density lipoproteins (LDLs) and increases in high-density lipoproteins (HDLs). Fifty-two healthy adults provided self-report data for social inclusion and blood samples for hematological tests. Results indicated that higher social inclusion predicted lower levels of blood glucose and LDL, but had no effect on HDL. Implications for theory and practice are discussed.

  18. 21 CFR 866.5600 - Low-density lipoprotein immunological test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

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

  19. [Study of low density lipoproteins in hyperlipoproteinemia by the method of double immunodiffusion].

    PubMed

    Nikitina, N A; Perova, N V; Proskuriakova, T V; Suchkova, S N; Kutateladze, N V

    1977-06-01

    By way of gel double immunodiffusion a certain heterogeneity of low density lipoproteins was observed to manifest itself in an additional band of immunoprecipitation. The incidence of this additional band does not exceed 1/3 of the cases of low density lipoproteins studies in normal individuals, while in those with ischaemic heart disease the additional band is found twice-thrice as often, the highest incidence being noted in patients with ischaemic heart disease and Type IIb hyperlipoproteinemia (93% of cases). The revealed immunochemical heterogeneity of low density lipoproteins was shown to be not connected with the appearance of any new, additional antigen in their structure. Most probably it is attributable to the presence of lipoprotein particles with a quantitatively different protein and lipid composition, probably of intermediate lipoprotein metabolites in blood plasma, or conformation changes in the structure of low density lipoproteins.

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

    USDA-ARS?s Scientific Manuscript database

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

  1. Antibodies against oxidized low density lipoproteins in pregnant women.

    PubMed

    Fialová, L; Mikulíková, L; Malbohan, I; Benesová, O; Stípek, S; Zima, T; Zwinger, A

    2002-01-01

    Oxidized low density lipoproteins (oxLDL) formed in vivo induce a humoral immune response. Oxidative modification of LDL renders it immunogenic and a heterogeneous population of specific anti-oxLDL antibodies is produced. These antibodies could represent a biological marker of oxidative stress and serve as markers of atherosclerosis. Autoantibodies against oxLDL (oLAb) have been detected in human subjects practically of every age. oLAb also appear in the blood of pregnant women. Some studies have shown that the levels of antibodies to oxLDL were elevated in women with established preeclampsia. The present study was aimed to estimate the oLAb IgG levels in the first and second trimester of pregnancy. Furthermore, we estimated the correlation between maternal serum (MS) levels of oLAb and alpha-1-fetoprotein (MS AFP), human chorionic gonadotrophin (MS HCG) and trophoblast-specific-beta-1-glycoprotein (MS SP1), because these proteins are determined as a part of prenatal biochemical screening for fetal congenital abnormalities. Our study deals with the oLAb changes in women with pregnancy-induced hypertension. We also investigated the correlation between oLAb IgG and anticardiolipin antibodies IgG (ACA) in the serum of pregnant women. We examined 40 pregnant women attending Institute for Mother and Child Care for their antenatal care as outpatients. Routine blood samplings between the 9-13th week of pregnancy and 16-18th week of pregnancy were performed as a part of biochemical prenatal screening for fetal congenital abnormalities (Group 1). Their mean age was 27 +/- 4.1 years. Furthermore, we examined 26 women in the second or third trimester with pregnancy-induced hypertension (Group 2). Group 2 was compared with 49 pregnant women in the second or third trimester who were normotensive (Group 3). We used commercial standardized ELISA kits for determination of oLAb IgG, ACA IgG, MS AFP and MS HCG, MS SP1 was analyzed by single radial immunodiffusion. We did not find

  2. A Mediterranean-style, low-glycemic-load diet decreases atherogenic lipoproteins and reduces lipoprotein (a) and oxidized low-density lipoprotein in women with metabolic syndrome.

    PubMed

    Jones, Jennifer L; Comperatore, Michael; Barona, Jacqueline; Calle, Mariana C; Andersen, Catherine; McIntosh, Mark; Najm, Wadie; Lerman, Robert H; Fernandez, Maria Luz

    2012-03-01

    The objective was to assess the impact of a Mediterranean-style, low-glycemic-load diet (control group, n = 41) and the same diet plus a medical food (MF) containing phytosterols, soy protein, and extracts from hops and Acacia (MF group, n = 42) on lipoprotein atherogenicity in women with metabolic syndrome. Plasma lipids, apolipoproteins (apos), lipoprotein subfractions and particle size, low-density lipoprotein (LDL) oxidation, and lipoprotein (a) were measured at baseline, week 8, and week 12 of the intervention. Three-day dietary records were collected at the same time points to assess compliance. Compared with baseline, women decreased energy intake from carbohydrate (P < .001) and fat (P < .001), whereas they increased energy intake from protein (P < .001). A significant increase in energy from monounsaturated fatty acids was also observed as well as increases in eicosapentaenoic acid and docosahexaenoic acid, whereas trans-fatty acid intake was reduced (P < .00001). The atherogenic lipoproteins, large very low-density lipoprotein (P < .0001) and small LDL (P < .0001), were reduced, whereas the ratio of large high-density lipoprotein to smaller high-density lipoprotein particles was increased (P < .0001). Apolipoprotein B was reduced for all women (P < .0001), with a greater reduction in the MF group (P < .025). Oxidized LDL (P < .05) and lipoprotein (a) (P < .001) were reduced in both groups at the end of the intervention. Consumption of a Mediterranean-style diet reduces the risk for cardiovascular disease by decreasing atherogenic lipoproteins, oxidized LDL, and apo B. Inclusion of an MF may have an additional effect in reducing apo B. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Linkage of low-density lipoprotein size to the lipoprotein lipase gene in heterozygous lipoprotein lipase deficiency.

    PubMed Central

    Hokanson, J E; Brunzell, J D; Jarvik, G P; Wijsman, E M; Austin, M A

    1999-01-01

    Small low-density lipoprotein (LDL) particles are a genetically influenced coronary disease risk factor. Lipoprotein lipase (LpL) is a rate-limiting enzyme in the formation of LDL particles. The current study examined genetic linkage of LDL particle size to the LpL gene in five families with structural mutations in the LpL gene. LDL particle size was smaller among the heterozygous subjects, compared with controls. Among heterozygous subjects, 44% were classified as affected by LDL subclass phenotype B, compared with 8% of normal family members. Plasma triglyceride levels were significantly higher, and high-density lipoprotein cholesterol (HDL-C) levels were lower, in heterozygous subjects, compared with normal subjects, after age and sex adjustment. A highly significant LOD score of 6.24 at straight theta=0 was obtained for linkage of LDL particle size to the LpL gene, after adjustment of LDL particle size for within-genotype variance resulting from triglyceride and HDL-C. Failure to adjust for this variance led to only a modest positive LOD score of 1.54 at straight theta=0. Classifying small LDL particles as a qualitative trait (LDL subclass phenotype B) provided only suggestive evidence for linkage to the LpL gene (LOD=1. 65 at straight theta=0). Thus, use of the quantitative trait adjusted for within-genotype variance, resulting from physiologic covariates, was crucial for detection of significant evidence of linkage in this study. These results indicate that heterozygous LpL deficiency may be one cause of small LDL particles and may provide a potential mechanism for the increase in coronary disease seen in heterozygous LpL deficiency. This study also demonstrates a successful strategy of genotypic specific adjustment of complex traits in mapping a quantitative trait locus. PMID:9973300

  4. Increased plasma peroxides and serum oxidized low density lipoprotein antibodies in major depression: markers that further explain the higher incidence of neurodegeneration and coronary artery disease.

    PubMed

    Maes, Michael; Mihaylova, Ivanka; Kubera, Marta; Uytterhoeven, Marc; Vrydags, Nicolas; Bosmans, Eugene

    2010-09-01

    Major depression is characterized by a decreased antioxidant status, an induction of the inflammatory and oxidative and nitrosative (IO&NS) pathways and inflammatory-neurodegenerative (I&ND) pathways. This study examines two markers of oxidative stress in depression, i.e. plasma peroxides and serum oxidized LDL (oxLDL) antibodies. Blood was sampled in 54 patients with major depression (mean+/-SD age=43.5+/-11.6 years) and 37 normal volunteers (43.6+/-11.1 years). The severity of illness was measured by means of the Hamilton Depression Rating Scale. The Fibromyalgia and Chronic Fatigue Syndrome Rating Scale was used to measure severity of "psychosomatic" symptoms in depression. We found significantly higher plasma peroxides (p=0.002) and serum oxLDL antibodies (p=0.0002) in depressed patients as compared to normal controls. There was no significant correlation between both markers and both independently from each other predicted major depression. There were significant correlations between the oxLDL antibodies and the scores on two items of the FF scale, i.e. gastro-intestinal symptoms and headache. The results show that major depression is accompanied by increased oxidative stress and lipid peroxidation. These results further extend the IO&NS pathophysiology of major depression. Since increased peroxides and oxLDL antibodies are predictors of coronary artery disease (CAD) and neurodegeneration, our findings suggest that IO&NS pathways are involved in the increased incidence of both CAD and neurodegeneration in depression. 2010 Elsevier B.V. All rights reserved.

  5. [THE LIPOLYSIS IN PHYLOGENETICALLY EARLY LIPOPROTEINS OF LOW DENSITY AND MORE LATER LIPOPROTEINS OF VERY LOW DENSITY: FUNCTION AND DIAGNOSTIC VALUE OF APOE AND APOC-III].

    PubMed

    Rozhkova, T A; Titov, V N; Amelyushkina, V A; Kaba, S I; Kukhartchuk, V V

    2015-12-01

    According to phylogenetic theory of general pathology, the function of low density lipoproteins (LDL) and hydrolysis of triglycerides (TG) in them under the effect of hepatic glycerol hydrolase apoC-III (HGH) developed at much earlier stages of phylogenesis than functioning of insulin-dependent phylogenetically late very low density lipoproteins (VLDL). For millions ofyears, lipolysis and HGH+apoC-III have activated transfer of polyenic fatty acids (FA) in the form of cholesteryl polyesters (CLE) from high density lipoproteins (HDL) to linoleic and linolenic LDL under the effect of cholesteryl ester transfer protein. It is reasonable to suggest that hepatocytes physiologically secrete oleic and palmitic VLDL and linoleic and linolenic LDL. Cells uptake ligand oleic and palmitic VLVL by apoE/B-100 receptor-mediated endocytosis. Physiologically, VLDL are not converted to LDL. If hepatocytes secrete palmitic VLDL in greater amounts than oleic VLDL upon slow hydrolysis ofpalmitic TG and under the effect of postheparinic lipoprotein lipase+apoC-II, only some proportion of palmitic TG is uptaken by cells as VLDL, and the rest is converted in ligand-free palmitic LDL These LDL increase plasma contents of TG and LDL-cholesterol and form small dense palmitic LDL. Expression of HGH+apoC-III synthesis compensates TG hydrolysis in nonphysiological palmitic LDL. In vivo, apoC-III is neither physiological no pathological inhibitor of lipolysis. Increase in plasma apoC-III content is an indicator of accumulation of non-physiological palmitic LDL and atherosclerosis-atheromatosis risk factor ApoE content ofpalmitic LDL increases together with apoC-III, i.e., apoE in ligand VLDL is not internalized via apoE/B-100 endocytosis. An increase in apoC-III and apoE contents are reliable in vivo tests for the rise inpalmitic FA, palmitic TG and excessive secretion of palmitic VLDL by hepatocytes. ApoC-III and apoE contents in LDL are additional tests to evaluate the efficiency of

  6. Identification of low density lipoprotein as a regulator of Fc receptor-mediated phagocytosis.

    PubMed Central

    Bigler, R D; Khoo, M; Lund-Katz, S; Scerbo, L; Esfahani, M

    1990-01-01

    Optimal expression of the high-affinity Fc receptor for IgG (FcRI) by the human monocyte cell line U-937 requires the presence of low density lipoprotein (LDL), and neither cholesterol nor high density lipoprotein can provide the component necessary for optimal FcRI expression. Here we show that FcR-mediated phagocytosis also requires LDL. U-937 cells were cultured in medium containing interferon gamma and either fetal calf serum (FCS) or delipidated FCS (DLFCS). The phagocytosis of IgG-coated erythrocytes was measured by a colorimetric assay. U-937 cells cultured in DLFCS medium had less than 16% of the phagocytic activity of cells cultured in normal FCS medium. Phagocytosis of IgG-coated erythrocytes could be inhibited 85% by the addition of murine IgG2a myeloma protein (5 micrograms/ml). U-937 cells cultured in DLFCS medium supplemented with pure cholesterol in ethanol (10 micrograms/ml) had only 30% of the phagocytic activity of cells grown in FCS medium. Addition of very low density lipoprotein (0.2 mg of protein per ml) to DLFCS medium also failed to increase phagocytosis. However, the addition of LDL (0.2 mg of protein per ml) to DLFCS medium restored 90% of the phagocytic activity. Since neither pure cholesterol nor very low density lipoprotein restored normal phagocytic function to U-937 cells despite a normalization of cellular cholesterol content, the restoration of phagocytosis observed with LDL replacement cannot be explained by mere delivery of cholesterol by LDL. Thus, LDL is required for the expression of FcRI and FcR-mediated phagocytosis by U-937 cells and may be an important regulator of phagocytic activity of monocytes and macrophages in vivo. PMID:2367519

  7. Distinct Hepatic Receptors for Low Density Lipoprotein and Apolipoprotein E in Humans

    NASA Astrophysics Data System (ADS)

    Hoeg, Jeffrey M.; Demosky, Stephen J.; Gregg, Richard E.; Schaefer, Ernst J.; Brewer, H. Bryan

    1985-02-01

    Since the liver is a central organ for lipid and lipoprotein synthesis and catabolism, hepatic receptors for specific apolipoproteins on plasma lipoproteins would be expected to modulate lipid and lipoprotein metabolism. The role of hepatic receptors for low density lipoproteins and apolipoprotein E-containing lipoproteins was evaluated in patients with complementary disorders in lipoprotein metabolism: abetalipoproteinemia and homozygous familial hypercholesterolemia. In addition, hepatic membranes from a patient with familial hypercholesterolemia were studied and compared before and after portacaval shunt surgery. The results establish that the human liver has receptors for apolipoproteins B and E. Furthermore, in the human, hepatic receptors for low density lipoproteins and apolipoprotein E are genetically distinct and can undergo independent control.

  8. Comparative Studies of Vertebrate Lipoprotein Lipase: A Key Enzyme of Very Low Density Lipoprotein Metabolism

    PubMed Central

    Holmes, Roger S; Vandeberg, John L; Cox, Laura A

    2011-01-01

    Lipoprotein lipase (LIPL or LPL; E.C.3.1.1.34) serves a dual function as a triglyceride lipase of circulating chylomicrons and very-low-density lipoproteins (VLDL) and facilitates receptor-mediated lipoprotein uptake into heart, muscle and adipose tissue. Comparative LPL amino acid sequences and protein structures and LPL gene locations were examined using data from several vertebrate genome projects. Mammalian LPL genes usually contained 9 coding exons on the positive strand. Vertebrate LPL sequences shared 58–99% identity as compared with 33–49% sequence identities with other vascular triglyceride lipases, hepatic lipase (HL) and endothelial lipase (EL). Two human LPL N-glycosylation sites were conserved among seven predicted sites for the vertebrate LPL sequences examined. Sequence alignments, key amino acid residues and conserved predicted secondary and tertiary structures were also studied. A CpG island was identified within the 5'-untranslated region of the human LPL gene which may contribute to the higher than average (x4.5 times) level of expression reported. Phylogenetic analyses examined the relationships and potential evolutionary origins of vertebrate lipase genes, LPL, LIPG (encoding EL) and LIPC (encoding HL) which suggested that these have been derived from gene duplication events of an ancestral neutral lipase gene, prior to the appearance of fish during vertebrate evolution. Comparative divergence rates for these vertebrate sequences indicated that LPL is evolving more slowly (2–3 times) than for LIPC and LIPG genes and proteins. PMID:21561822

  9. [In vitro immunosuppressive effect of low density lipoproteins].

    PubMed

    González, M; Sanz, I; Rojas, N; Silva, V; Kirsten, L; Bustamante, M

    1999-11-01

    Immune cells participate in the formation of atheromatous plate, however little is known about the effects of native or oxidatively modified lipoproteins on these cells. To study the effects of lipoproteins on in vitro mononuclear cell proliferation. Peripheral blood mononuclear cells were obtained from 10 patients with type 2 diabetes mellitus (aged 52 +/- 9 years old with a disease duration of 8.2 +/- 5.7 years and a mean glycosilated hemoglobin of 9.3 +/- 2.2%) and 10 non diabetic healthy controls (aged 50.3 +/- 7.1 years old). These were stimulated with phytohemagglutinin (PHA) alone or in the presence of native LDLS, malondialdehyde modified LDLs or glycated LDLs. Proliferation was measured as 3H-thymidine incorporation and expressed as Stimulation Index (SI). SI of patients and healthy subjects, after PHA stimulation were similar: (57.5 +/- 29.8 and 61.1 +/- 23.5) respectively LDLs did not induce proliferation in neither group. Native LDLs produced a 98% inhibition of PHA induced proliferation. Malondialdehyde modified and glycated LDLs caused a 50% inhibition. The suppressive effect was maintained when lipoproteins were incorporated to culture media 60 min prior or after PHA stimulation. Lipoproteins inhibit in vitro PHA induced peripheral blood mononuclear cell proliferation both in diabetic and in non diabetic subjects.

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

    PubMed Central

    Gibbons, G F

    1990-01-01

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

  11. Kinetics of in vitro lipolysis of human very low-density lipoprotein by lipoprotein lipase.

    PubMed

    Schreier, L; Berg, G; Zago, V; Gonzalez, A I; Wikinski, R

    2002-02-01

    An initial step in the catabolism of triglyceride-rich lipoprotein involves the hydrolysis of the triglyceride moiety by lipoprotein lipase (LPL). As differences in the lipolytic behaviour of very low-density lipoprotein (VLDL) particles have been observed, it is possible that different VLDL particles have a different affinity to the enzyme, which means that their fate may partially depend on the LPL-mediated hydrolysis of their triglyceride content. Our aim was to determine whether variation in VLDL chemical composition affects their properties as a substrate for LPL. Isolated VLDL was incubated in vitro with bovine LPL to determine substrate affinity. Under optimal assay conditions, free fatty acids were measured and the kinetic indicators for in vitro triglyceride hydrolysis (Km and Vmax) were calculated. VLDL cholesterol (VLDL-C), VLDL-apoB and the cholesterol/triglyceride ratio were assessed and the triglyceride/protein and triglyceride/apoB ratios were calculated as lipoprotein size estimators. VLDL-C, VLDL-apoB and the VLDL-C/triglyceride ratio positively correlated with Km: r = 0.52, p < 0.01; r = 0.52, p < 0.03; r = 0.69, p < 0.001 respectively. No correlation was found between the VLDL-triglyceride/protein or the VLDL-triglyceride/apoB ratios and Km (r = -0.20, and -0.06 respectively, p = not significant). Of the subjects' anthropometric characteristics, only the waist/hip ratio significantly correlated with Km: r = 0.63, p < 0.01. In the present study, we investigated the substrate function of VLDL particles in vitro. Enzyme affinity seems to be associated with cholesterol-triglyceride content or the number of VLDL particles rather than particle size. It may be expected that VLDL with a low cholesterol/triglyceride ratio will be efficiently lypolised by LPL, thus leading to the formation of a smaller particle with atherogenic potential.

  12. Ceruloplasmin as low-density lipoprotein oxidase: activation by ascorbate and dehydroascorbate.

    PubMed

    Feichtenhofer, S; Fabjan, J S; Abuja, P M

    2001-07-13

    The ability of ceruloplasmin (Cp) to oxidize low-density lipoproteins (LDL) in the presence of water-soluble antioxidants was investigated and a reaction mechanism proposed. Ascorbate strongly enhanced LDL oxidation, but only after its rapid consumption. Dehydroascorbate enhanced Cp-mediated LDL oxidation even more strongly. Lipid-soluble antioxidants and water-soluble peroxides did not show noticeable activation. However, loading of LDL with lipid hydroperoxides increased the initial oxidation rate. We conclude that Cp mediates a localized redox cycle, where reduction of Cp-Cu2+ is effected by water-soluble reductants and reoxidation by liposoluble hydroperoxides.

  13. Transport of Very Low Density Lipoprotein Triglycerides in Varying Degrees of Obesity and Hypertriglyceridemia

    PubMed Central

    Grundy, Scott M.; Mok, Henry Y. I.; Zech, Loren; Steinberg, Daniel; Berman, Mones

    1979-01-01

    Measurements of transport of triglycerides (TG) in very low density lipoproteins (VLDL) were carried out in 59 patients by injection of radioactive glycerol, determinations of specific activities of VLDL-TG for 48 h thereafter, and treatment of the data by multicompartmental analysis. The patients were divided into three groups: normal weight (89-120% ideal weight), mildly obese (120-135% ideal weight), and markedly obese (135% ideal weight). They had varying levels of VLDL-TG ranging from normal to markedly elevated. In many subjects, there was a positive correlation between concentrations and transport of VLDL indicating that overproduction of VLDL-TG contributed to hypertriglyceridemia. In others, and particularly in several markedly obese subjects, transport rates were greatly increased without significant hypertriglyceridemia, suggesting that they had enhanced capacity to clear TG. In all groups, however, there were patients whose degree of hypertriglyceridemia seemed out of proportion to their transport rates. This finding and the fact that many patients have increased secretion of VLDL-TG without elevated plasma TG suggests that both overproduction of VLDL-TG and insufficient enhancement of clearance contributed to the development of hypertriglyceridemia. The data showed a poor correlation between transport rates determined by our multicompartment analysis and single-exponential analysis used previously by other investigators (r = 0.46); this comparison was not improved by segregating patients according to their degree of obesity. Although two conversion pathways (fast and slow synthetic paths) were required to fit the data, there was no correlation between transport rates and the ratio of the two pathways. Also, despite the known pathway of conversion of VLDL to low density lipoprotein, no correlation was found between VLDL-TG transport rates and estimated low density lipoprotein-cholesterol concentrations. PMID:221538

  14. Phagocytosis of aggregated lipoprotein by macrophages: Low density lipoprotein receptor-dependent foam-cell formation

    SciTech Connect

    Suits, A.G.; Chait, A.; Aviram, M.; Heinecke, J.W. )

    1989-04-01

    Low density lipoprotein (LDL) modified by incubation with phospholipase C (PLC-LDL) aggregates in solution and is rapidly taken up and degraded by human and mouse macrophages, producing foam cells in vitro. Human, mouse, and rabbit macrophages degraded {sup 125}I-labeled PLC-LDL ({sup 125}I-PLC-LDL) more rapidly than native {sup 125}I-labeled LDL ({sup 125}I-LDL), while nonphagocytic cells such as human fibroblasts and bovine aortic endothelial cells degraded {sup 125}I-PLC-LDL more slowly than {sup 125}I-LDL. This suggested the mechanism for internalization of PLC-LDL was phagocytosis. When examined by electron microscopy, mouse peritoneal macrophages appeared to be phagocytosing PLC-LDL. The uptake and degradation of {sup 125}I-PLC-LDL by human macrophages was inhibited >80% by the monoclonal antibody C7 (IgG2b) produced by hybridoma C7, which blocks the ligand binding domain of the LDL receptor. Similarly, methylation of {sup 125}I-LDL ({sup 125}I-MeLDL) prior to treatment with phospholipase C decreased its subsequent uptake and degradation by human macrophages by >90%. The uptake and degradation of phospholipase C-modified {sup 125}I-MeLDL by macrophages could be restored by incubation of the methylated lipoprotein with apoprotein E, a ligand recognized by the LDL receptor. These results indicate that macrophages internalize PLC-LDL by LDL receptor-dependent phagocytosis.

  15. Effects of oxidation on the structure and stability of human low-density lipoprotein.

    PubMed

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

    2007-05-15

    Oxidation of low-density lipoprotein (LDL), the major cholesterol carrier in plasma, is thought to promote atherogenesis via several mechanisms. One proposed mechanism involves fusion of oxidized LDL in the arterial wall; another involves oxidation-induced amyloid formation by LDL apolipoprotein B. To test these mechanisms and to determine the effects of oxidation on the protein secondary structure and lipoprotein fusion in vitro, we analyzed LDL oxidized by nonenzymatic (Cu2+, H2O2, and HOCl) or enzymatic methods (myeloperoxidase/H2O2/Cl- and myeloperoxidase/H2O2/NO2-). Far-UV circular dichroism spectra showed that LDL oxidation induces partial unfolding of the secondary structure rather than folding into cross-beta amyloid conformation. This unfolding correlates with increased negative charge of oxidized LDL and with a moderate increase in thioflavin T fluorescence that may result from electrostatic attraction between the cationic dye and electronegative LDL rather than from dye binding to amyloid. These and other spectroscopic studies of low- and high-density lipoproteins, which encompass amyloid-promoting conditions (high protein concentrations, high temperatures, acidic pH), demonstrate that in vitro lipoprotein oxidation does not induce amyloid formation. Surprisingly, turbidity, near-UV circular dichroism, and electron microscopic data demonstrate that advanced oxidation inhibits heat-induced LDL fusion that is characteristic of native lipoproteins. Such fusion inhibition may result from the accumulation of anionic lipids and lysophospholipids on the particle surface and/or from protein cross-linking upon advanced lipoprotein oxidation. Consequently, oxidation alone may prevent rather than promote LDL fusion, suggesting that additional factors, such as albumin-mediated removal of lipid peroxidation products and/or LDL binding to arterial proteoglycans, facilitate fusion of oxidized LDL in vivo.

  16. Normalisation of the composition of very low density lipoprotein in hypertriglyceridemia by nicotinic acid.

    PubMed

    Tornvall, P; Hamsten, A; Johansson, J; Carlson, L A

    1990-10-01

    Large (Sf greater than 100) and small (Sf 100-20) very low density lipoprotein (VLDL) particles were isolated by density gradient ultracentrifugation and characterized chemically in 8 patients with primary hypertriglyceridemia before and after 6 weeks treatment with 4 grammes daily of nicotinic acid (NA). Concomitant changes in high density lipoprotein (HDL) subclass distribution were determined by gradient gel electrophoresis. Small VLDL was subjected to lipolysis in vitro by incubation with bovine lipoprotein lipase before and after NA, and the change in the lipolytic end-product isolated in the low density lipoprotein (LDL) fraction was investigated. Reductions were achieved in the plasma levels of triglycerides, free and esterified cholesterol, phospholipids and proteins in the two VLDL subfractions. In all, the composition of both large and small VLDL particles changed towards potentially less atherogenic particles that were poorer in cholesteryl esters. The HDL cholesterol concentration increased and the HDL protein distribution on gradient gel electrophoresis changed towards larger particles. The mechanism behind the change in cholesterol distribution between VLDL and HDL after NA treatment is unclear, but it could possibly relate to decreased lipid transfer activity. NA reduced the content of apolipoprotein B in both VLDL subclasses and did not decrease the calculated particle size or the number of triglyceride molecules per particle, indicating a reduction of VLDL particle number rather than of particle size. The LDL density fraction isolated after lipolysis in vitro of small VLDL contained less total cholesterol and phospholipids and had a density profile more similar to native LDL after the patients had been treated with NA.

  17. [Effect of rations with an increased sunflower seed oil level on the rate of very low-density lipoprotein formation in the liver, secretion into the blood and composition in the blood].

    PubMed

    Liapkov, B G

    1978-01-01

    Feeding of rats on a ration with an excessive content of sunflower-oil (60 per cent of the total calorific value of the ration) for a period of 30 days resulted in lowering the rate of the apoproteins, prolipoproteins synthesis in the liver and in their loading with triglycerides and cholesterol. As a consequence of this it diminished secretion of endogenously formed tryglycerides and cholesterol from the liver into the blood and a changed lipid composition of lipoproteins of a very low density in the blood.

  18. Generation in Human Plasma of Misfolded, Aggregation-Prone Electronegative Low Density Lipoprotein

    PubMed Central

    Greco, Giulia; Balogh, Gabor; Brunelli, Roberto; Costa, Graziella; De Spirito, Marco; Lenzi, Laura; Mei, Giampiero; Ursini, Fulvio; Parasassi, Tiziana

    2009-01-01

    Abstract Human plasma contains small amounts of a low density lipoprotein in which apoprotein is misfolded. Originally identified and isolated by means of anion-exchange chromatography, this component was subsequently described as electronegative low density lipoprotein (LDL)(−), with increased concentrations associated with elevated cardiovascular disease risk. It has been recognized recently as the trigger of LDL amyloidogenesis, which produces aggregates similar to subendothelial droplets observed in vivo in early atherogenesis. Although LDL(−) has been produced in vitro through various manipulations, the mechanisms involved in its generation in vivo remain obscure. By using a more physiological model, we demonstrate spontaneous, sustained and noticeable production of LDL(−) during incubation of unprocessed human plasma at 37°C. In addition to a higher fraction of amyloidogenic LDL(−), LDL purified from incubated plasma contains an increased level of lysophospholipids and free fatty acids; analysis of LDL lipids packing shows their loosening. As a result, during plasma incubation, lipid destabilization and protein misfolding take place, and aggregation-prone particles are generated. All these phenomena can be prevented by inhibiting calcium-dependent secretory phospholipases A2. Our plasma incubation model, without removal of reaction products, effectively shows a lipid-protein interplay in LDL, where lipid destabilization after lipolysis threatens the apoprotein's structure, which misfolds and becomes aggregation-prone. PMID:19619478

  19. Amphotericin B toxicity as related to the formation of oxidatively modified low-density lipoproteins.

    PubMed

    Barwicz, J; Dumont, I; Ouellet, C; Gruda, I

    1998-01-01

    The effect of amphotericin B on the oxidation and degradation of low- and high-density lipoproteins was investigated by UV-vis spectroscopy, electron microscopy, electrophoresis, and size-exclusion chromatography. Two formulations of the drug were used: the commercial Fungizone and a new, less toxic, liposomal formulation, AmBisome. It was shown that Fungizone strongly enhanced the oxidative deformation of low-density lipoprotein structure while AmBisome did not bind to this lipoprotein fraction and did not affect its oxidation. It was shown that amphotericin B contained in Fungizone extracted cholesterol from low-density lipoproteins which sensitized them to oxidation. Both formulations of amphotericin B studied here did not bind to high-density lipoprotein and did not affect the process of its oxidation.

  20. Native low density lipoprotein promotes lipid raft formation in macrophages.

    PubMed

    Song, Jian; Ping, Ling-Yan; Duong, Duc M; Gao, Xiao-Yan; He, Chun-Yan; Wei, Lei; Wu, Jun-Zhu

    2016-03-01

    Oxidized low‑density lipoprotein (LDL) has an important role in atherogenesis; however, the mechanisms underlying cell‑mediated LDL oxidation remain to be elucidated. The present study investigated whether native‑LDL induced lipid raft formation, in order to gain further insight into LDL oxidation. Confocal microscopic analysis revealed that lipid rafts were aggregated or clustered in the membrane, which were colocalized with myeloperoxidase (MPO) upon native LDL stimulation; however, in the presence of methyl‑β‑cyclodextrin (MβCD), LDL‑stimulated aggregation, translocation, and colocalization of lipid rafts components was abolished.. In addition, lipid raft disruptors MβCD and filipin decreased malondialdehyde expression levels. Density gradient centrifugation coupled to label‑free quantitative proteomic analysis identified 1,449 individual proteins, of which 203 were significantly upregulated following native‑LDL stimulation. Functional classification of the proteins identified in the lipid rafts revealed that the expression levels of translocation proteins were upregulated. In conclusion, the results of the present study indicated that native‑LDL induced lipid raft clustering in macrophages, and the expression levels of several proteins were altered in the stimulated macrophages, which provided novel insights into the mechanism underlying LDL oxidation.

  1. Effects of low dose oral contraceptives on very low density and low density lipoprotein metabolism.

    PubMed Central

    Walsh, B W; Sacks, F M

    1993-01-01

    Oral contraceptives (OC) raise plasma triglyceride and VLDL levels, which may be of concern, since some conditions characterized by elevated triglycerides are associated with atherosclerosis. To identify the responsible mechanism, we studied 11 healthy premenopausal women, 5 of whom were taking OC containing 0.035 mg ethinyl estradiol, and 6 of whom were not. Their rates of VLDL and LDL metabolism were measured by endogenously labeling apoB, the protein component of VLDL and LDL, by an intravenous infusion of deuterated leucine. OC use had the greatest effect on the large, triglyceride-rich VLDL subfraction (Sf 60-400), increasing plasma levels threefold and production rates fivefold (P < 0.05). Among OC users, small VLDL (Sf 20-60) levels were 2.2 times higher, and production rates were 3.4-fold higher (P < 0.05). The fractional catabolic rates of large and small VLDL were similar among OC users and nonusers. LDL levels and metabolic rates were not significantly different between the two groups. Thus, contemporary low dose OC substantially raise VLDL levels by increasing the production rate of large, triglyceride-rich VLDL, and not by slowing VLDL catabolism. Since VLDL catabolism is not impaired, we speculate that the hypertriglyceridemia induced by OC may be less atherogenic than that of hypertriglyceridemia resulting from impaired lipolysis. This may explain why long-term OC use does not appear to promote atherosclerosis. PMID:8486779

  2. Apolipoprotein AII Is a Regulator of Very Low Density Lipoprotein Metabolism and Insulin Resistance*

    PubMed Central

    Castellani, Lawrence W.; Nguyen, Cara N.; Charugundla, Sarada; Weinstein, Michael M.; Doan, Chau X.; Blaner, William S.; Wongsiriroj, Nuttaporn; Lusis, Aldons J.

    2008-01-01

    Apolipoprotein AII (apoAII) transgenic (apoAIItg) mice exhibit several traits associated with the insulin resistance (IR) syndrome, including IR, obesity, and a marked hypertriglyceridemia. Because treatment of the apoAIItg mice with rosiglitazone ameliorated the IR and hypertriglyceridemia, we hypothesized that the hypertriglyceridemia was due largely to overproduction of very low density lipoprotein (VLDL) by the liver, a normal response to chronically elevated insulin and glucose. We now report in vivo and in vitro studies that indicate that hepatic fatty acid oxidation was reduced and lipogenesis increased, resulting in a 25% increase in triglyceride secretion in the apoAIItg mice. In addition, we observed that hydrolysis of triglycerides from both chylomicrons and VLDL was significantly reduced in the apoAIItg mice, further contributing to the hypertriglyceridemia. This is a direct, acute effect, because when mouse apoAII was injected into mice, plasma triglyceride concentrations were significantly increased within 4 h. VLDL from both control and apoAIItg mice contained significant amounts of apoAII, with ∼4 times more apoAII on apoAIItg VLDL. ApoAII was shown to transfer spontaneously from high density lipoprotein (HDL) to VLDL in vitro, resulting in VLDL that was a poorer substrate for hydrolysis by lipoprotein lipase. These results indicate that one function of apoAII is to regulate the metabolism of triglyceride-rich lipoproteins, with HDL serving as a plasma reservoir of apoAII that is transferred to the triglyceride-rich lipoproteins in much the same way as VLDL and chylomicrons acquire most of their apoCs from HDL. PMID:18160395

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

    PubMed Central

    Bays, Harold E

    2014-01-01

    Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia, insulin resistance, and/or progressive loss of β-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

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

    PubMed

    Bays, Harold E

    2014-01-01

    Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia, insulin resistance, and/or progressive loss of β-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.

  5. Phosphatidylinositol turnover in mitogen-activated lymphocytes. Suppression by low-density lipoproteins

    PubMed Central

    Hui, David Y.; Harmony, Judith A. K.

    1980-01-01

    Low-density (LD) lipoproteins inhibit phytohaemagglutinin-enhanced turnover of phosphatidylinositol in human peripheral lymphocytes. Turnover was assessed by 32P incorporation into phospholipids and by loss of 32P from [32P]phosphatidylinositol. Inhibition of lipid turnover by LD lipoproteins is not the result of a change in the amount of phytohaemagglutinin required for maximum cellular response. Neither phytohaemagglutinin nor LD lipoproteins influence 32P incorporation into phosphatidylethanolamine and phosphatidylcholine during the first 60min after mitogenic challenge. The extent of inhibition of phosphatidylinositol turnover by LD lipoproteins depends on the concentration of LD lipoproteins present in the incubation medium: 50% of maximum inhibition occurs at a low-density-lipoprotein protein concentration of 33μg/ml and maximum inhibition occurs at low-density-lipoprotein protein concentrations above 100μg/ml. Phytohaemagglutinin stimulates 32P incorporation into phosphatidylinositol, phosphatidylinositol phosphate and phosphatidylinositol bisphosphate. However, LD lipoproteins abolish 32P incorporation into phosphatidylinositol without affecting incorporation into phosphatidylinositol phosphate and phosphatidylinositol bisphosphate. The ability of LD lipoproteins to inhibit phytohaemagglutinin-induced phosphatidylinositol turnover is mimicked by EGTA. Furthermore, inhibition of LD lipoproteins by phytohaemagglutinin-induced 32P incorporation into phosphatidylinositol correlates directly with inhibition by LD lipoproteins of Ca2+ accumulation. These results suggest that Ca2+ accumulation and turnover of phosphatidylinositol are coupled responses in lymphocytes challenged by mitogens. The step in phosphatidylinositol metabolism that is sensitive to LD lipoproteins and, by inference, that is coupled to Ca2+ accumulation is release of [32P]phosphoinositol from phosphatidylinositol. PMID:6796039

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

    USDA-ARS?s Scientific Manuscript database

    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...

  7. d-alpha-Tocopherol inhibits low density lipoprotein induced proliferation and protein kinase C activity in vascular smooth muscle cells.

    PubMed

    Ozer, N K; Palozza, P; Boscoboinik, D; Azzi, A

    1993-05-17

    Native and malondialdehyde modified low density lipoproteins have been shown to stimulate smooth muscle cell proliferation (A7r5) in vitro. The stimulation is associated with an increase of protein kinase C activity. d-alpha-Tocopherol, at physiological concentrations, has been found to inhibit both protein kinase C activity and cell proliferation.

  8. Low-density lipoprotein cholesterol and the risk of dementia with stroke.

    PubMed

    Moroney, J T; Tang, M X; Berglund, L; Small, S; Merchant, C; Bell, K; Stern, Y; Mayeux, R

    1999-07-21

    Next to Alzheimer disease, vascular dementia is the second most common form of dementia in the elderly, yet few specific risk factors have been identified. To investigate the relationship of plasma lipids and lipoproteins to dementia with stroke. Prospective longitudinal community-based study over a 7-year period (1991-1998). A total of 1111 nondemented participants (mean [SD] age, 75.0 [5.9] years) were followed up for an average of 2.1 years (range, 1-7.8 years). Incident dementia with stroke according to standardized criteria, by baseline levels of total plasma cholesterol and triglycerides, low-density lipoprotein (LDL) cholesterol, LDL levels corrected for lipoprotein(a), high-density lipoprotein cholesterol, lipoprotein(a), and apolipoprotein E genotype. Two hundred eighty-six (25.7%) of the 1111 subjects developed dementia during follow-up; 61 (21.3%) were classified as having dementia with stroke and 225 (78.7%) as having probable Alzheimer disease. Levels of LDL cholesterol were significantly associated with an increased risk of dementia with stroke. Compared with the lowest quartile, the highest quartile of LDL cholesterol was associated with an approximately 3-fold increase in risk of dementia with stroke, adjusting for vascular risk factors and demographic variables (relative risk [RR], 3.1; 95% confidence interval [CI], 1.5-6.1). Levels of LDL corrected for lipoprotein(a) were an even stronger predictor of dementia with stroke in the adjusted multivariate analysis. Compared with the lowest quartile, the RR of dementia with stroke for the highest quartile of lipoprotein(a)-corrected LDL cholesterol was 4.1 (95% CI, 1.8-9.6) after adjusting for vascular factors and demographic variables. Lipid or lipoprotein levels were not associated with the development of Alzheimer disease in our cohort. Elevated levels of LDL cholesterol were associated with the risk of dementia with stroke in elderly patients. Further study is needed to determine whether treatment

  9. Proteome of human plasma very low-density lipoprotein and low-density lipoprotein exhibits a link with coagulation and lipid metabolism.

    PubMed

    Dashty, M; Motazacker, M M; Levels, J; de Vries, M; Mahmoudi, M; Peppelenbosch, M P; Rezaee, F

    2014-03-03

    Apart from transporting lipids through the body, the human plasma lipoproteins very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) are also thought to serve as a modality for intra-organismal protein transfer, shipping proteins with important roles in inflammation and thrombosis from the site of synthesis to effector locations. To better understand the role of VLDL and LDL in the transport of proteins, we applied a combination of LTQ ORBITRAP-XL (nLC-MS/MS) with both in-SDS-PAGE gel and in-solution tryptic digestion of pure and defined VLDL and LDL fractions. We identified the presence of 95 VLDL- and 51 LDL-associated proteins including all known apolipoproteins and lipid transport proteins, and intriguingly a set of coagulation proteins, complement system and anti- microbial proteins. Prothrombin, protein S, fibrinogen γ, PLTP, CETP, CD14 and LBP were present on VLDL but not on LDL. Prenylcysteine oxidase 1, dermcidin, cathelicidin antimicrobial peptide, TFPI-1 and fibrinogen α chain were associated with both VLDL and LDL. Apo A-V is only present on VLDL and not on LDL. Collectively, this study provides a wealth of knowledge on the protein constituents of the human plasma lipoprotein system and strongly supports the notion that protein shuttling through this system is involved in the regulation of biological processes. Human diseases related to proteins carried by VLDL and LDL can be divided in three major categories: 1 - dyslipidaemia, 2 - atherosclerosis and vascular disease, and 3 - coagulation disorders.

  10. Liver-specific inactivation of the abetalipoproteinemia gene completely abrogates very low density lipoprotein/low density lipoprotein production in a viable conditional knockout mouse.

    PubMed

    Chang, B H; Liao, W; Li, L; Nakamuta, M; Mack, D; Chan, L

    1999-03-05

    Conventional knockout of the microsomal triglyceride transfer protein large subunit (lMTP) gene is embryonic lethal in the homozygous state in mice. We have produced a conditional lMTP knockout mouse by inserting loxP sequences flanking exons 5 and 6 by gene targeting. Homozygous floxed mice were born live with normal plasma lipids. Intravenous injection of an adenovirus harboring Cre recombinase (AdCre1) produced deletion of exons 5 and 6 and disappearance of lMTP mRNA and immunoreactive protein in a liver-specific manner. There was also disappearance of plasma apolipoprotein (apo) B-100 and marked reduction in apoB-48 levels. Wild-type mice showed no response, and heterozygous mice, an intermediate response, to AdCre1. Wild-type mice doubled their plasma cholesterol level following a high cholesterol diet. This hypercholesterolemia was abolished in AdCre1-treated lMTP-/- mice, the result of a complete absence of very low/intermediate/low density lipoproteins and a slight reduction in high density lipoprotein. Heterozygous mice showed an intermediate lipoprotein phenotype. The rate of accumulation of plasma triglyceride following Triton WR1339 treatment in lMTP-/- mice was <10% that in wild-type animals, indicating a failure of triglyceride-rich lipoprotein production. Pulse-chase experiments using hepatocytes isolated from wild-type and lMTP-/- mice revealed a failure of apoB secretion in lMTP-/- animals. Therefore, the liver-specific inactivation of the lMTP gene completely abrogates apoB-100 and very low/intermediate/low density lipoprotein production. These conditional knockout mice are a useful in vivo model for studying the role of MTP in apoB biosynthesis and the biogenesis of apoB-containing lipoproteins.

  11. [Very low density lipoproteins and subclasses of intermediate density lipoproteins in postmenopausal women].

    PubMed

    Berg, G; Halperín, H; Siseles, N; Wikinski, R

    1996-01-01

    Post menopausal women present an increase of cardiovascular risk associated with the atherogenic plasma lipoproteins IDL and LDL. Our purpose was to study the composition of VLDL, IDL and the subfractions IDL-1 and IDL-2, and the Lipoprotein Lipase and Hepatic Lipase activities in a group of twelve healthy post menopausal women as compared with eleven fertile controls. The mean values of total cholesterol and LDL cholesterol were significantly increased in the post menopausal group compared to the controls (p < 0.005 and p < 0.001 respectively). The contribution of the HDL-cholesterol plasma concentration to total cholesterol was lower in the postmenopausal women (p < 0.02) although no one had HDL-cholesterol lower than 35 mg/dl and the mean value was 50 mg/dl. Postmenopausal women had increased concentrations of VLDL, total IDL and IDL-2 compared to controls (p < 0.05, p < 0.005 and p < 0.001 respectively). Plasma concentrations of total IDL was increased in postmenopausal women (33.6 +/- 3.4 vs 22.6 +/- 0.8 mg/dl, p < 0.005). The increase in total IDL was due to IDL-2 (19.9 +/- 1.7 vs 11.5 +/- 0.8 mg/dl, p < 0.001, in postmenopausal women vs controls). The IDL-2 subfraction was 60 +/- 2.6% of total IDL in postmenopausal women and 51 +/- 2.0% in controls (p < 0.02). In postmenopausal women and in controls the ratio triglyceride/protein (which indicates particles size) was significantly higher in IDL-1 than in IDL-2 (p < 0.005 and p < 0.01 respectively), but this ratio did not show differences when VLDL, total IDL and IDL-2 were compared between postmenopausal and control women. Then, the increased plasma concentration of these lipoproteins would show an increased number of particles in the postmenopausal women vs controls. There were no differences in the Lipoprotein Lipase and Hepatic Lipase activities between both groups. Lipoprotein Lipase vs total IDL-triglycerides and IDL-2-triglycerides showed a significant inverse correlation in controls (p < 0.05) but not

  12. Prenylcysteine oxidase 1, a pro-oxidant enzyme of low density lipoproteins.

    PubMed

    Herrera-Marcos, Luis V; Lou-Bonafonte, Jose M; Martinez-Gracia, Maria V; Arnal, Carmen; Navarro, María A; Osada, Jesus

    2018-01-01

    Elevated levels of low density lipoproteins (LDLs) cause atherosclerotic disease, and proteomic analyses have found that these lipoproteins are endowed with prenylcysteine lyase. This systematic review summarizes current understanding of this enzyme, now known as prenylcysteine oxidase 1 (PCYOX1), which hydrolyzes the thioether bond of prenylcysteines in the final step in the degradation of prenylated proteins, releasing hydrogen peroxide, cysteine and the isoprenoid aldehyde. Despite the high variability of the PCYOX1 gene, no polymorphism has yet been associated with any disease. The liver, which is responsible for vehiculization of the enzyme in lipoproteins, is one of the main organs responsible for its expression, together with the gastrointestinal tract, kidney, male reproductive tissue and muscle. Moreover, although hepatic mRNA expression is sensitive to diet and hormones, the repercussion of these changes in LDLs containing PCYOX1 has not been addressed. One consequence of its elevated activity could be an increase in hydrogen peroxide, which might help to propagate the oxidative burden of LDLs, thus making PCYOX1 a potential pharmacological target and a new biomarker in cardiovascular disease.

  13. Lectin-like oxidized low-density lipoprotein receptor (LOX-1) in sickle cell disease vasculopathy

    PubMed Central

    Chen, Mingyi; Qiu, Hong; Lin, Xin; Nam, David; Ogbu-Nwobodo, Lucy; Archibald, Hannah; Joslin, Amelia; Wun, Ted; Sawamura, Tatsuya; Green, Ralph

    2017-01-01

    Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) is an endothelial receptor for oxidized LDL. Increased expression of LOX-1 has been demonstrated in atherosclerotic lesions and diabetic vasculopathy. In this study, we investigate the expression of LOX-1 receptor in sickle cell disease (SCD) vasculopathy. Expression of LOX-1 in brain vascular endothelium is markedly increased and LOX-1 gene expression is upregulated in cultured human brain microvascular endothelial cells by incubation with SCD erythrocytes. Also, the level of circulating soluble LOX-1 concentration is elevated in the plasma of SCD patients. Increased LOX-1 expression in endothelial cells is potentially involved in the pathogenesis of SCD vasculopathy. Soluble LOX-1 concentration in SCD may provide a novel biomarker for risk stratification of sickle cell vascular complications. PMID:27519944

  14. Lectin-like oxidized low-density lipoprotein receptor (LOX-1) in sickle cell disease vasculopathy.

    PubMed

    Chen, Mingyi; Qiu, Hong; Lin, Xin; Nam, David; Ogbu-Nwobodo, Lucy; Archibald, Hannah; Joslin, Amelia; Wun, Ted; Sawamura, Tatsuya; Green, Ralph

    2016-09-01

    Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) is an endothelial receptor for oxidized LDL. Increased expression of LOX-1 has been demonstrated in atherosclerotic lesions and diabetic vasculopathy. In this study, we investigate the expression of LOX-1 receptor in sickle cell disease (SCD) vasculopathy. Expression of LOX-1 in brain vascular endothelium is markedly increased and LOX-1 gene expression is upregulated in cultured human brain microvascular endothelial cells by incubation with SCD erythrocytes. Also, the level of circulating soluble LOX-1 concentration is elevated in the plasma of SCD patients. Increased LOX-1 expression in endothelial cells is potentially involved in the pathogenesis of SCD vasculopathy. Soluble LOX-1 concentration in SCD may provide a novel biomarker for risk stratification of sickle cell vascular complications.

  15. Monoclonal antibodies to human plasma low-density lipoproteins. I. Enhanced binding of 125I-labeled low-density lipoproteins by combined use of two monoclonal antibodies.

    PubMed

    Mao, S J; Patton, J G; Badimon, J J; Kottke, B A; Alley, M C; Cardin, A D

    1983-11-01

    Four monoclonal antibodies (IgG2b) to human plasma low-density lipoproteins (LDL) have been characterized. The binding affinities of each monoclonal antibody to 125I-labeled LDL were moderately high, ranging from 10(8) to 10(10) L/mol at 4 degrees C, but were reduced by at least 50-70% at 37 degrees C. The maximum binding of each monoclonal antibody was unique, ranging from 20 to 95% of total 125I-labeled LDL, suggesting that LDL particles were immunochemically heterogeneous. One antibody, LP-34, had both high and low binding affinities to LDL. Another, LP-47, exhibited high affinity for isolated LDL, yet reacted poorly with native LDL in plasma, indicating that the conformation of isolated LDL differs from that of native LDL in plasma. Unlike polyclonal serum antibodies, a mixture of four monoclonal antibodies failed to precipitate LDL, but did show a drastic increase in binding to LDL. We found that only two of our monoclonal antibodies were necessary for such synergistic enhancement. We propose that one of the monoclonal antibodies may serve as a catalytic reagent, and discuss the clinical significance of this finding.

  16. Activation of 15-lipoxygenase by low density lipoprotein in vascular endothelial cells. Relationship to the oxidative modification of low density lipoprotein.

    PubMed

    Derian, C K; Lewis, D F

    1992-01-01

    Oxidatively-modified low density lipoprotein (LDL) is thought to play a significant role in the formation of lipid-laden macrophages, the primary cellular component of atherosclerotic fatty lesions. Recently, lipoxygenases have been implicated as a major enzymatic pathway involved in rabbit endothelial cell-mediated LDL modification. We investigated the effect of LDL on porcine aortic endothelial cell (PAEC) and human umbilical vein (HUVEC) and aortic endothelial cell (HAEC) lipoxygenase activity. By thin layer chromatography, we observed that human LDL stimulated the metabolism of radiolabeled arachidonic acid to 12 + 15-hydroxyeicosatetraenoic acid (HETE) in indomethacin-treated PAEC. Furthermore, radiolabeled linoleic acid, a specific substrate for the 15-lipoxygenase, was metabolized to its respective product 13-hydroxyoctadecadienoic acid (13-HODE) in the presence of LDL. Increased product formation in both studies was inhibited by the lipoxygenase blockers nordihydroguaiaretic acid (NDGA) and RG 6866. 15-HETE was confirmed as the predominant HETE product in LDL-treated cells by high performance liquid chromatography. Both porcine- and human-derived LDL stimulated the CL release of 15-HETE from cells as determined by radioimmunoassay. Release of immunoreactive 15-HETE was inhibited by NDGA, RG 6866, and 5,8,11,14-eicosatetraynoic acid (ETYA) but not by the selective 5-lipoxygenase inhibitor RG 5901. These lipoxygenase inhibitors had similar effects on the modification of LDL. Our results suggest that the oxidative modification of LDL by endothelial cells may be mediated in part through activation of 15-lipoxygenase.

  17. Effect of improving glycemic control in patients with type 2 diabetes mellitus on low-density lipoprotein size, electronegative low-density lipoprotein and lipoprotein-associated phospholipase A2 distribution.

    PubMed

    Sánchez-Quesada, José L; Vinagre, Irene; de Juan-Franco, Elena; Sánchez-Hernández, Juan; Blanco-Vaca, Francisco; Ordóñez-Llanos, Jordi; Pérez, Antonio

    2012-07-01

    The aim of this study was to determine the effect of intensified hypoglycemic therapy in patients with type 2 diabetes mellitus on the distribution of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity between high-density lipoprotein and low-density lipoprotein (LDL) and its relation with the lipid profile and other qualitative properties of LDL. Forty-two patients with type 2 diabetes on the basis of poor glycemic control and normal or near normal LDL cholesterol were recruited. Lifestyle counseling and pharmacologic hypoglycemic therapy were intensified to improve glycemic control, but lipid-lowering therapy was unchanged. At 4 ± 2 months, glycosylated hemoglobin had decreased by a mean of 2.1%, but the only effect on the lipid profile were statistically significant decreases in nonesterified fatty acids and apolipoprotein B concentration. LDL size increased and the proportion of electronegative LDL decreased significantly. In parallel, total Lp-PLA2 activity decreased significantly, promoting a redistribution of Lp-PLA2 activity toward a higher proportion in high-density lipoprotein. Improvements in glycemic control led to more marked changes in Lp-PLA2 activity and distribution in patients with diabetes who had not received previous lipid-lowering therapy. In conclusion, optimizing glycemic control in patients with type 2 diabetes promotes atheroprotective changes, including larger LDL size, decreased electronegative LDL, and a higher proportion of Lp-PLA2 activity in high-density lipoprotein.

  18. New low-density lipoprotein receptor upregulators acting via a novel mechanism.

    PubMed

    Ashton, M J; Brown, T J; Fenton, G; Halley, F; Harper, M F; Lockey, P M; Porter, B; Roach, A G; Stuttle, K A; Vicker, N; Walsh, R J

    1996-08-16

    The synthesis and biological activity of a new series of benzamides and related compounds that upregulate the expression of the low-density lipoprotein (LDL) receptor in human hepatocytes (HepG2 cells) by a novel mechanism are described. The lead compound, N-[5-[(3-cyclohexylpropionyl)amino]-2-methylphenyl]-4-hydroxybe nzamide (1, RPR102359), increased the expression of the LDL receptors in HepG2 cells by 80% when tested at a concentration of 3 microM. Mevinolin (lovastatin) was found to increase the LDL receptor expression by 70% at the same concentration. In contrast to mevinolin, 1 was found to have no effect on cholesterol biosynthesis in liver homogenates or in HepG2 cells at doses where substantial upregulation of the LDL receptor was observed and thus stimulated LDL receptor expression by a novel mechanism.

  19. Soy constituents: modes of action in low-density lipoprotein management.

    PubMed

    van Ee, Jan H

    2009-04-01

    Reviewed here are the modes of action of soy components used as ingredients in foods, which can lower plasma levels of low-density lipoprotein (LDL) and cholesterol, which are markers for the risk for atherosclerosis. Soy ingredients act via more than one mode of action including the following: LDL absorption suppression, cholesterol efflux stimulation, LDL resorption stimulation, LDL oxidation prevention, LDL particle size increase, cholesterol synthesis reduction, and bile secretion increase. Individual genetics, lifestyle, and nutrition habits alter LDL management and a better understanding of the various modes of actions of soy ingredients may facilitate the composition of effective ingredient cocktails. The optimization of food components offers further alternatives to LDL management to augment drug therapy for patients who are unable to reach their target LDL cholesterol levels or who are suffering from side effects or drug insensitivity.

  20. Very low density lipoproteins in intestinal lymph: role in triglyceride and cholesterol transport during fat absorption

    PubMed Central

    Ockner, Robert K.; Hughes, Faith B.; Isselbacher, Kurt J.

    1969-01-01

    The role of nonchylomicron very low density lipoproteins (VLDL, Sf 20-400) in the transport of triglyceride and cholesterol was studied during lipid absorption. Various long chain fatty acids were infused intraduodenally in the form of mixed fatty acid—mono-olein-taurocholate micelles; control animals received saline or taurocholate. As compared with controls, all fatty acids (palmitic, oleic, linoleic) resulted in significant increases in chylomicron (Sf > 400) triglyceride. In addition, palmitic acid resulted in a twofold increase in VLDL triglyceride, whereas with the absorption of oleic or linoleic acid VLDL triglyceride did not change significantly. Differences in triglyceride fatty acid composition between chylomicrons and VLDL were observed during lipid absorption. Although the absolute amount of endogenous cholesterol in intestinal lymph was not significantly affected by lipid absorption under these conditions, its lipoprotein distribution differed substantially among the lipid-infused groups. During palmitate absorption, VLDL cholesterol was similar to that in the taurocholate-infused controls, and was equal to chylomicron cholesterol. In contrast, during oleate and linoleate absorption the VLDL cholesterol fell markedly, and was less than half of the chylomicron cholesterol in these groups. The half-time of plasma survival of VLDL cholesterol-14C was found to be twice that of chylomicron cholesterol-14C. These studies demonstrate that dietary long chain fatty acids differ significantly in their effects upon the transport of triglyceride and cholesterol by lipoproteins of rat intestinal lymph. These findings, together with the observed differences in rates of removal of chylomicrons and VLDL from plasma, suggest that variations in lipoprotein production at the intestinal level may be reflected in differences in the subsequent metabolism of absorbed dietary and endogenous lipids. PMID:5355348

  1. Novel fluorescent probe for low density lipoprotein, based on the enhancement of Europium emission band

    NASA Astrophysics Data System (ADS)

    Courrol, L. C.; Monteiro, A. M.; Silva, F. R. O.; Gomes, L.; Vieira, N. D., Jr.; Gidlund, M. A.; Figueiredo Neto, A. M.

    2007-05-01

    We report here the observation of the enhancement of Europium-tetracycline complex emission in Low Density Lipoprotein (LDL) solutions. Europium emission band of tetracycline solution containing Europium (III) chloride hexahydrate was tested to obtain effective enhancement in the presence of native LDL and oxidized LDL. Europium emission lifetime in the presence of lipoproteins was measured, resulting in a simple method to measure the lipoproteins quantity in an aqueous solution at physiological pH. This method shows that the complex can be used as a sensor to determine the different states of native and oxidized LDL in biological fluids.

  2. Obstructive jaundice leads to accumulation of oxidized low density lipoprotein in human liver tissue.

    PubMed

    Comert, Mustafa; Ustundag, Yucel; Tekin, Ishak Ozel; Gun, Banu Dogan; Barut, Figen

    2006-08-21

    Oxidized low density lipoprotein (ox-LDL) molecule is one of the most important modified lipoproteins produced during the oxidative stress. Modified lipoproteins have been defined as being part of the immune inflammatory mechanisms in association with oxidant stress. We have reported the accumulation of ox-LDL in Balb/c mice liver after bile duct ligation previously. Here, we investigated this finding in human beings with obstructive jaundice. Our study demonstrates that obstructive jaundice results in tremendous accumulation of ox-LDL in the liver tissue of patients.

  3. High systemic levels of low-density lipoprotein cholesterol: fuel to the flames in inflammatory osteoarthritis?

    PubMed

    de Munter, Wouter; van der Kraan, Peter M; van den Berg, Wim B; van Lent, Peter L E M

    2016-01-01

    There is increasing evidence that low-density lipoprotein (LDL) cholesterol plays a role in the pathology of OA. Specifically, oxidized LDL (oxLDL), which has been shown to play an essential role during development of atherosclerosis, could be involved in processes such as synovial inflammation, cartilage destruction and bone deformations. OxLDL can activate synovial cells such as macrophages, endothelial cells and synovial fibroblasts, resulting in release of growth factors, MMP and pro-inflammatory cytokines. In this review article, we discuss the role of LDL and oxLDL in OA joint pathology and share our viewpoint of possible mechanisms by which these proteins could influence the development and progression of OA. The proposed theory could provide insight into the aetiopathology of OA and give rise to new potential treatments.

  4. Edaravone attenuates monocyte adhesion to endothelial cells induced by oxidized low-density lipoprotein.

    PubMed

    Li, Zhijuan; Cheng, Jianxin; Wang, Liping

    2015-10-30

    Oxidized low-density lipoprotein (oxLDL) plays a vital role in recruitment of monocytes to endothelial cells, which is important during early stages of atherosclerosis development. Edaravone, a potent and novel scavenger of free radicals inhibiting hydroxyl radicals, has been clinically used to reduce the neuronal damage following ischemic stroke. In the present study, Edaravone was revealed to markedly reduce oxLDL-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). The inhibitory mechanism of Edaravone was associated with suppression of the chemokine MCP-1 and adhesion molecule VCAM-1 and ICAM-1 expression. In addition, luciferase reporter assay results revealed that administration of Edaravone attenuated the increase in NF-κB transcriptional activity induced by oxLDL. Notably, it's also shown that Edaravone treatment blocked oxLDL induced p65 nuclear translocation in HUVECs. Results indicate that Edaravone negatively regulates endothelial inflammation.

  5. Influence of the environment in space on the biochemical characteristics of human low density lipoproteins.

    PubMed

    Dousset, N; Moatti, J P; Moatti, N; Degré, M; Eche, B; Gasset, G; Tixador, R

    1996-01-01

    The purpose of this experiment was to study the efficiency of protective substances on the effects of cosmic radiation in space on low density lipoproteins. This environment induced modifications in LDL consisting of an increase of lipid peroxidation markers (hydroperoxides, thiobarbituric acid reactive substances). In contrast, apo B was not affected by cosmic radiation as shown by the stability of the trinitrobenzenesulfonic acid reactivity and the tryptophan content. Furthermore, oxidation of LDL was partially inhibited by the addition of cysteamine or/and probucol before the spaceflight experiment. The hydroperoxide formation was almost completely inhibited by cysteamine. It was concluded that antioxidants can exert a protective effect against peroxidative stress induced by the space environment.

  6. Low density lipoprotein receptor related protein 1 variant interacts with saturated fatty acids in Puerto Ricans

    USDA-ARS?s Scientific Manuscript database

    Low density lipoprotein related receptor protein 1 (LRP1) is a multi-functional endocytic receptor that is highly expressed in adipocytes and the hypothalamus. Animal models and in vitro studies support a role for LRP1 in adipocyte metabolism and leptin signaling, but genetic polymorphisms have not ...

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

    USDA-ARS?s Scientific Manuscript database

    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...

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

    USDA-ARS?s Scientific Manuscript database

    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...

  9. Separation of apolipoproteins of human very low density lipoproteins by chromatofocusing.

    PubMed

    März, W; Gross, W

    1983-07-01

    Chromatofocusing represents a new chromatographic procedure for the separation of proteins according to their isoelectric points. We describe the application of this method for the fractionation of the urea-soluble apolipoproteins of very low density lipoproteins. They were separated into five peaks, four of which were homogeneous as judged by polyacrylamide gel electrophoresis in the presence of 7 mol/l urea.

  10. 21 CFR 866.5600 - Low-density lipoprotein immunological test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Low-density lipoprotein immunological test system. 866.5600 Section 866.5600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological Test Systems §...

  11. 21 CFR 866.5600 - Low-density lipoprotein immunological test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Low-density lipoprotein immunological test system. 866.5600 Section 866.5600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological Test Systems §...

  12. A green tea catechin extract upregulates the hepatic low-density lipoprotein receptor in rats.

    PubMed

    Bursill, Christina A; Roach, Paul D

    2007-07-01

    Green tea extracts have hypocholesterolaemic properties in epidemiological and animal intervention studies. Upregulation of the low-density lipoprotein (LDL) receptor may be one mechanism to explain this as it is the main way cholesterol is removed from the circulation. This study aimed to determine if a green tea extract could upregulate the hepatic LDL receptor in vivo in the rat. A green tea extract (GTE) enriched in its anti-oxidant constituents, the catechins, was fed to rats (n = 6) at concentrations of either 0, 0.5, 1.0 or 2.0% (w/w) mixed in with their normal chow along with 0.25% (w/w) cholesterol for 12 days. Administration of the GTE had no effect on plasma total or LDL cholesterol concentrations but high-density lipoprotein significantly increased (41%; p < 0.05). Interestingly, there was a significant increase in LDL receptor binding activity (2.7-fold) and LDL receptor protein (3.4-fold) in the 2% (w/w) treatment group compared to controls. There were also significant reductions in liver total and unesterified cholesterol (40%). Administration of the GTE significantly reduced cholesterol absorption (24%) but did not affect cholesterol synthesis. These results show that, despite no effect on plasma cholesterol, the GTE upregulated the LDL receptor in vivo. This appears to be via a reduction in liver cholesterol concentration and suggests that the green tea extract was able to increase the efflux of cholesterol from liver cells.

  13. Effects of estrogen on very low-density lipoprotein triglyceride metabolism in fed and fasted chicks

    SciTech Connect

    Park, J.R.

    1988-01-01

    A single injection of estrogen into growing chicks resulted in a marked elevation in plasma triglyceride (TG) followed by phospholipid (PL) and cholesterol (CH) in both fed and fasted chicks. Estrogen caused a development of massive fatty liver in fed chicks. Hepatic malic enzyme and glucose-6-phosphate dehydrogenase activities also increased significantly in fed chicks and, to a small extent, in fasted chicks. Very low density lipoproteins (VLDL) were barely detectable in the fasted control plasma. However, the VLDL concentration increased markedly upon estrogen injection, becoming the most prevalent lipoprotein in the plasma. The administration of estrogen resulted in an increase in oleic acid and a decrease in linoleic acid content except in the cholesteryl ester of VLDL and LDL. VLDL of estrogenized birds had {beta}-mobility on agarose gel electrophoresis, and they eluted in two peaks on agarose gel filtration chromatography. Both peaks on gel filtration exhibited the same {beta}-mobility on agarose gel electrophoresis. Nevertheless, the apoprotein composition of these two peaks were substantially different from each other; apo B was not present in the first peak VLDL. VLDL-TG kinetic studies conducted in vivo, using {sup 14}C-TG-VLDL prepared endogenously from control and estrogenized chicks revealed that VLDL-TG produced from the former had a higher fractional catabolic rate (FCR) than VLDL-TG from the latter.

  14. Detection of oxidized low-density lipoproteins in gingival crevicular fluid from dental patients.

    PubMed

    Sakiyama, Y; Kato, R; Inoue, S; Suzuki, K; Itabe, H; Yamamoto, M

    2010-04-01

    Oxidative modification of low-density lipoprotein (LDL) occurs in various diseased tissues and sites of local inflammation. For example, an increased plasma oxidized low-density lipoprotein (OxLDL) level is a well-known risk marker for cardiovascular diseases. Gingival crevicular fluid, the exudate from gingival tissues into the sulci, can be easily collected in a non-invasive manner. However, the possible presence of OxLDL in gingival crevicular fluid has not been studied. In this study, we established a procedure to measure OxLDL in human gingival crevicular fluid. Human gingival crevicular fluid was sampled with paper points or paper strips. The gingival crevicular fluid samples from healthy gingival sulci (pocket depth < 4 mm, n = 14) were subjected to western blot and/or sandwich ELISA. The amounts of OxLDL and LDL were measured by sandwich ELISA using an anti-oxidized phosphatidylcholine monoclonal antibody and two anti-apolipoprotein B antibodies. Venous blood samples were analyzed biochemically. We tested two methods of gingival crevicular fluid collection, namely paper points and paper strips. Gingival crevicular fluid could be collected very safely with paper points and they showed good recovery of LDL and OxLDL throughout the analysis. Apolipoprotein B, the major protein component in LDL, was detected in gingival crevicular fluid by western blot, and OxLDL was found to be present in gingival crevicular fluid by ELISA. The OxLDL/LDL ratio in gingival crevicular fluid was 17.0 times higher than that in plasma. This is the first report to show the presence of apolipoprotein B and apolipoprotein B- oxidized phosphatidylcholine complex, which correspond to LDL and OxLDL, respectively, in gingival crevicular fluid.

  15. Minimally oxidized low-density lipoprotein induces tissue factor expression in cultured human endothelial cells.

    PubMed Central

    Drake, T. A.; Hannani, K.; Fei, H. H.; Lavi, S.; Berliner, J. A.

    1991-01-01

    Oxidatively modified low-density lipoprotein is present in atherosclerotic lesions and has been proposed to play an important role in atherogenesis through its biologic effects on vascular cells. This study examined the effects of minimally oxidized preparations of LDL (MM-LDL) on tissue factor (TF) expression by cultured human endothelial cells. Low-density lipoprotein purified from normal donors was modified by exposure to iron or by prolonged storage, resulting in levels of thiobarbituric acid-reacting substances of approximately 2.5 to 4 nmoles/mg cholesterol. Preparations had less than 2.5 pg of endotoxin per microgram LDL and had no intrinsic procoagulant activity. This form of modified but not native LDL induced TF expression in endothelial cells in a time- and dose-dependent manner. Peak TF coagulant activity in cells exposed to 40 micrograms/ml MM-LDL were observed at 4 to 6 hours, and ranged from 50 to 500 pg/10(5) cells, compared with less than 10 pg/10(5) cells exposed to native LDL. Northern blot analysis showed TF mRNA levels to increase approximately 30-fold with exposure to MM-LDL for 2 hours. Induction of TF activity was dependent on the concentration of MM-LDL from 1 microgram/ml to 80 micrograms/ml, a range in which cell viability and morphology were unaffected. The findings suggest that minimally oxidized LDL may be a local mediator promoting thrombosis in atherosclerotic lesions. Images Figure 1 PMID:2000938

  16. Overexpression of LOXIN Protects Endothelial Progenitor Cells From Apoptosis Induced by Oxidized Low Density Lipoprotein.

    PubMed

    Veas, Carlos; Jara, Casandra; Willis, Naomi D; Pérez-Contreras, Karen; Gutierrez, Nicolas; Toledo, Jorge; Fernandez, Paulina; Radojkovic, Claudia; Zuñiga, Felipe A; Escudero, Carlos; Aguayo, Claudio

    2016-04-01

    Human endothelial progenitor cells (hEPC) are adult stem cells located in the bone marrow and peripheral blood. Studies have indicated that hEPC play an important role in the recovery and repair of injured endothelium, however, their quantity and functional capacity is reduced in several diseases including hypercholesterolemia. Recently, it has been demonstrated that hEPC express lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its activation by oxidized low-density lipoprotein (ox-LDL) induces cellular dysfunction and apoptosis. This study aimed to investigate whether overexpression of LOXIN, a truncated isoform of LOX-1 that acts as a dominant negative, plays a protective role against ox-LDL-induced apoptosis in hEPC. Human endothelial progenitor cells exposed to ox-LDL showed a significant increase in LOX-1 expression, and apoptosis began at ox-LDL concentrations above 50 μg/mL. All hEPC apoptosed at 200 μg/mL ox-LDL. High LOXIN expression was generated using adenoviral systems in hEPC and SiHa cells transduced with 100 colony-forming units per cell. Transduced LOXIN localized to the plasma membrane and blocked ox-LDL uptake mediated by LOX-1. Overexpression of LOXIN protected hEPC from ox-LDL-induced apoptosis, and therefore maybe a novel way of improving hEPC function and quantity. These results suggest that adenoviral vectors of LOXIN may provide a possible treatment for diseases related to ox-LDL and vascular endothelium dysfunction, including atherosclerosis.

  17. LIPOPROTEIN LIPASE RELEASES ESTERIFIED OXYLIPINS FROM VERY LOW-DENSITY LIPOPROTEINS.

    USDA-ARS?s Scientific Manuscript database

    Defects in lipoprotein metabolism alter the lipoprotein distribution of oxidized PUFAs, and we speculate that lipoprotein lipase (LpL) is a determinant in the release of VLDL-associated oxylipins. Here, using 12 wk old normolipidemic (lean) and hyperlipidemic (obese) Zucker-rats, we measured PUFA al...

  18. Expression of scavenger receptor-BI and low-density lipoprotein receptor and differential use of lipoproteins to support early steroidogenesis in luteinizing macaque granulosa cells.

    PubMed

    Cherian-Shaw, Mary; Puttabyatappa, Muraly; Greason, Erin; Rodriguez, Annabelle; VandeVoort, Catherine A; Chaffin, Charles L

    2009-02-01

    An ovulatory hCG stimulus to rhesus macaques undergoing controlled ovarian stimulation protocols results in a rapid and sustained increase in progesterone synthesis. The use of lipoproteins as a substrate for progesterone synthesis remains unclear, and the expression of lipoprotein receptors [very-low-density lipoprotein receptor (VLDLR), low-density lipoprotein receptor (LDLR), and scavenger receptor-BI (SR-BI)] soon after human chorionic gonadotropin (hCG) (<12 h) has not been characterized. This study investigated lipoprotein receptor expression and lipoprotein (VLDL, LDL, and HDL) support of steroidogenesis during luteinization of macaque granulosa cells. Granulosa cells were aspirated from rhesus monkeys undergoing controlled ovarian stimulation before or up to 24 h after an ovulatory hCG stimulus. The expression of VLDLR decreased within 3 h of hCG, whereas LDLR and SR-BI increased at 3 and 12 h, respectively. Granulosa cells isolated before hCG were cultured for 24 h in the presence of FSH or FSH plus hCG with or without VLDL, LDL, or HDL. Progesterone levels increased in the presence of hCG regardless of lipoprotein addition, although LDL, but not HDL, further augmented hCG-induced progesterone. Other cells were cultured with FSH or FSH plus hCG without an exogenous source of lipoprotein for 24 h, followed by an additional 24 h culture with or without lipoproteins. Cells treated with hCG in the absence of any lipoprotein were unable to maintain progesterone levels through 48 h, whereas LDL (but not HDL) sustained progesterone synthesis. These data suggest that an ovulatory stimulus rapidly mobilizes stored cholesterol esters for use as a progesterone substrate and that as these are depleted, new cholesterol esters are obtained through an LDLR- and/or SR-BI-mediated mechanism.

  19. Role of dietary supplements in lowering low-density lipoprotein cholesterol: a review.

    PubMed

    Nijjar, Prabhjot S; Burke, Frances M; Bloesch, Annette; Rader, Daniel J

    2010-01-01

    Coronary heart disease (CHD) remains a major source of morbidity and mortality. As the epidemic of obesity, diabetes, and hypertension continues to grow among young adults, the population at risk for atherosclerotic CHD is ever increasing. More than a century of laboratory and human findings link cholesterol levels with a propensity to develop atherosclerosis. Low-density lipoprotein (LDL) is the major atherogenic lipoprotein, and numerous clinical trials have shown the efficacy of lowering LDL-cholesterol (LDL-C) for reducing CHD risk. New trial data have resulted in LDL-C goals being lowered over time and expansion of the population of patients that are candidates for LDL-lowering therapy to decrease their lifetime risk of CHD. Although statins are relatively safe and well tolerated, there are still significant numbers of patients who cannot tolerate them and many others who only require mild LDL-C reduction and prefer nonprescription alternatives to statin therapy. A number of dietary supplements and functional foods have been suggested to reduce LDL-C levels, but only a few have withstood the rigors of randomized controlled trials. Here we review the evidence in support of dietary supplements and their LDL-C-lowering effects. We also review supplements that, after initial excitement about their purported effect, were not found to lower LDL-C significantly. Copyright © 2010 National Lipid Association. Published by Elsevier Inc. All rights reserved.

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

    NASA Astrophysics Data System (ADS)

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

    2008-04-01

    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.

  1. Protective effect of oleanolic acid on oxidized-low density lipoprotein induced endothelial cell apoptosis.

    PubMed

    Cao, Jianhua; Li, Guanghui; Wang, Meizhi; Li, Hui; Han, Zhiwu

    2015-10-01

    Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid, OA) is a naturally-occurring triterpenoid with various promising pharmacological properties. The present study was conducted to determine the protective effects of OA against oxidized low-density lipoprotein (ox-LDL) induced endothelial cell apoptosis and the possible underlying mechanisms. Our results showed that ox-LDL significantly decreased cell viability and induced apoptosis in human umbilical vein endothelial cells (HUVECs). OA in the co-treatment showed a protective effect against ox-LDL induced loss in cell viability and an increase in apoptosis, which was associated with the modulating effect of OA on ox-LDL induced hypoxia-inducible factor 1α(HIF-1α) expression. Moreover, our results showed that the modulating effect of OA against ox-LDL induced HIF-1α expression was obtained via inhibition of lipoprotein receptor 1 (LOX-1)/reactive oxygen species (ROS) signaling. Collectively, we suggested that the protective effect of OA against ox-LDL induced HUVEC apoptosis might, at least in part, be obtained via inhibition of the LOX-1/ROS/HIF-1α signaling pathway.

  2. Enzymatically Modified Low-Density Lipoprotein Promotes Foam Cell Formation in Smooth Muscle Cells via Macropinocytosis and Enhances Receptor-Mediated Uptake of Oxidized Low-Density Lipoprotein.

    PubMed

    Chellan, Bijoy; Reardon, Catherine A; Getz, Godfrey S; Hofmann Bowman, Marion A

    2016-06-01

    Enzyme-modified nonoxidized low-density lipoprotein (ELDL) is present in human atherosclerotic lesions. Our objective is to understand the mechanisms of ELDL uptake and its effects on vascular smooth muscle cells (SMC). Transformation of murine aortic SMCs into foam cells in response to ELDL was analyzed. ELDL, but not acetylated or oxidized LDL, was potent in inducing SMC foam cell formation. Inhibitors of macropinocytosis (LY294002, wortmannin, amiloride) attenuated ELDL uptake. In contrast, inhibitors of receptor-mediated endocytosis (dynasore, sucrose) and inhibitor of caveolae-/lipid raft-mediated endocytosis (filipin) had no effect on ELDL uptake in SMC, suggesting that macropinocytosis is the main mechanism of ELDL uptake by SMC. Receptor for advanced glycation end products (RAGE) is not obligatory for ELDL-induced SMC foam cell formation, but primes SMC for the uptake of oxidized LDL in a RAGE-dependent manner. ELDL increased intracellular reactive oxygen species, cytosolic calcium, and expression of lectin-like oxidized LDL receptor-1 in wild-type SMC but not in RAGE(-/-) SMC. The macropinocytotic uptake of ELDL is regulated predominantly by intracellular calcium because ELDL uptake was completely inhibited by pretreatment with the calcium channel inhibitor lacidipine in wild-type and RAGE(-/-) SMC. This is in contrast to pretreatment with PI3 kinase inhibitors which completely prevented ELDL uptake in RAGE(-/-) SMC, but only partially in wild-type SMC. ELDL is highly potent in inducing foam cells in murine SMC. ELDL endocytosis is mediated by calcium-dependent macropinocytosis. Priming SMC with ELDL enhances the uptake of oxidized LDL. © 2016 American Heart Association, Inc.

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

    PubMed Central

    2014-01-01

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

  4. Lipolysis Produces Changes in the Immunoreactivity and Cell Reactivity of Very Low Density Lipoproteins

    PubMed Central

    Schonfeld, G.; Patsch, W.; Pfleger, B.; Witztum, J. L.; Weidman, S. W.

    1979-01-01

    Smaller very low density lipoprotein (VLDL) remnants interact more readily with tissues than do larger “intact” VLDL. This may be related to changes in the availability of VLDL apoproteins on the surface of the lipoproteins. To test this hypothesis VLDL were incubated at 37°C with bovine milk lipase (LPL), and the abilities of LPL-treated VLDL preparations to compete with 125I-low density lipoproteins (LDL) for interaction with cultured normal human fibroblasts were measured. At the same time, the immunologic activities of these preparations were also tested by double antibody radioimmunoassay. Triglyceride (TG) contents of VLDL fell by 30-90% during incubation with LPL and, on zonal ultracentrifugation, VLDL of faster Svedberg unit of flotation (Sf1.063) rates (>150) were gradually converted to smaller VLDL with lower Sf rates (21-60). LPL-treated VLDL competed two to five times more effectively with 125I-LDL for binding to cellular receptors than did control VLDL. Control VLDL incubated with heat-inactivated LPL at 37°C, or with active LPL at 4°C had unaltered cell reactivities and TG contents compared with VLDL incubated without any enzyme. The direct uptake and degradation of LPL-treated VLDL was also assessed by using VLDL 125I-labeled in apoprotein (Apo)B. LPL-treated VLDL-125I-ApoB were taken up and degraded by fibroblast at greater rates than were control VLDL-125I-ApoB. Thus, hydrolysis of VLDL lipids was accompanied by an increased ability of VLDL to interact with fibroblasts. The immunoreactivity of ApoB in the same VLDL preparations, expressed as the “apparent ApoB contents” of LPL-treated VLDL, increased by 10-50% (P < 0.02) in those assays that contained anti-LDL antisera, but the ApoB of control VLDL remained constant. However, assays that contained antisera directed against ApoB isolated from VLDL did not distinguish between LPL-treated and control VLDL. Thus, VLDL lipid hydrolysis was accompanied by changes in the immunoreactivity of

  5. Low density lipoprotein uptake by an endothelial-smooth muscle cell bilayer

    SciTech Connect

    Alexander, J.J.; Miguel, R.; Graham, D. )

    1991-03-01

    To study the interaction of endothelial and smooth muscle cells, and the means by which such interaction may affect lipid permeability of the arterial wall, cell bilayers were established by use of a transwell culture system. After confluent growth of both cell types had been achieved, iodine 125 bound to low-density lipoprotein (10 ng protein/ml) was added to the media of the upper well. After a 3-hour incubation period, the iodine 125-bound low-density lipoprotein content of the upper and lower media demonstrated an impedance to lipoprotein movement across the endothelial cell monolayer as compared to the bare porous polycarbonate filter of the transwell (p less than 10(-6)). The presence of smooth muscle cells in the bottom well significantly enhanced the permeability of the endothelial cell layer (p less than 10(-60)). This effect remained unchanged over a 9-day time course. Membrane binding and cellular uptake of low-density lipoprotein by endothelial cells was not altered by smooth muscle cells, indicating that this change in permeability could not be easily attributed to changes in receptor-mediated transport or transcytosis. Membrane binding (p less than 0.02) and cellular uptake (p less than 10(-6)) of low-density lipoprotein by smooth muscle cells in the bilayer, when adjusted for counts available in the smooth muscle cell media, were both reduced in the early incubation period as compared to isolated smooth muscle cells. The disproportionate reduction in uptake as compared to binding would suggest that this was not entirely a receptor-dependent process.

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

    PubMed Central

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

    1988-01-01

    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

  7. Comparison of apoprotein B of low density lipoproteins of human interstitial fluid and plasma.

    PubMed

    Hong, J L; Pflug, J; Reichl, D

    1984-08-15

    Virtually all apoprotein B (apoB)-containing lipoproteins of the peripheral interstitial fluid of subjects with primary lymphoedema float in the ultracentrifugal field in the density interval 1.019-1.063 g/ml; in this respect they are similar to plasma low-density lipoproteins (LDL). 2. Virtually all apo-B-containing lipoproteins of interstitial fluid migrate in the electrophoretic field with pre-beta mobility; in this respect they are similar to plasma very-low-density lipoproteins. 3. The apoB of lipoproteins of interstitial fluid does not differ in terms of Mr from apoB-100 of human plasma [Kane, Hardman & Paulus (1980) Proc. Natl. Acad. Sci. U.S.A. 77, 2465-2469] as determined by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. 4. Both apoB of interstitial fluid and plasma are heterogenous in terms of their charge as determined by isoelectric focusing of their complexes with the nonionic detergent Nonidet P40. ApoB of plasma LDL focuses between pH5.9 and 6.65, and that of interstitial fluid LDL between pH 5.9 and 6.1. Thus the overall charge of apoB of interstitial fluid is more negative than that of its plasma LDL counterpart.

  8. Enzymatic Modification of Plasma Low Density Lipoproteins in Rabbits: A Potential Treatment for Hypercholesterolemia

    NASA Astrophysics Data System (ADS)

    Labeque, Regine; Mullon, Claudy J. P.; Ferreira, Joao Paulo M.; Lees, Robert S.; Langer, Robert

    1993-04-01

    Phospholipase A_2 (EC 3.1.1.4) hydrolyzes certain phospholipids of low density lipoprotein (LDL). Plasma clearance of phospholipase A_2-modified human LDL is up to 17 times faster than that of native human LDL in hypercholesterolemic rabbits. Modification of blood lipoproteins of hypercholesterolemic rabbits was performed by using an extracorporeal circuit containing immobilized phospholipase A_2. After 90-min treatments, nearly 30% decreases in plasma cholesterol concentrations were observed. Erythrocyte, leukocyte, and platelet counts showed no net change after treatment. This technique does not require any fluid replacement or sorbent regeneration and offers a potential approach for lowering serum cholesterol and LDL levels.

  9. Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease.

    PubMed

    Varbo, Anette; Benn, Marianne; Smith, George Davey; Timpson, Nicholas J; Tybjaerg-Hansen, Anne; Nordestgaard, Børge G

    2015-02-13

    Obesity leads to increased ischemic heart disease (IHD) risk, but the risk is thought to be mediated through intermediate variables and may not be caused by increased weight per se. To test the hypothesis that the increased IHD risk because of obesity is mediated through lipoproteins, blood pressure, glucose, and C-reactive protein. Approximately 90 000 participants from Copenhagen were included in a Mendelian randomization design with mediation analyses. Associations were examined using conventional measurements of body mass index and intermediate variables and using genetic variants associated with these. During ≤22 years of follow-up 13 945 participants developed IHD. The increased IHD risk caused by obesity was partly mediated through elevated levels of nonfasting remnant cholesterol and low-density lipoprotein cholesterol, through elevated blood pressure, and possibly also through elevated nonfasting glucose levels; however, reduced high-density lipoprotein cholesterol and elevated C-reactive protein levels were not mediators in genetic analyses. The 3 intermediate variables that explained the highest excess risk of IHD from genetically determined obesity were low-density lipoprotein cholesterol with 8%, systolic blood pressure with 7%, and remnant cholesterol with 7% excess risk of IHD. Corresponding observational excess risks using conventional body mass index were 21%, 11%, and 20%, respectively. The increased IHD risk because of obesity was partly mediated through elevated levels of nonfasting remnant and low-density lipoprotein cholesterol and through elevated blood pressure. Our results suggest that there may be benefit to gain by reducing levels of these risk factors in obese individuals not able to achieve sustained weight loss. © 2014 American Heart Association, Inc.

  10. A dietary portfolio: maximal reduction of low-density lipoprotein cholesterol with diet.

    PubMed

    Kendall, Cyril W C; Jenkins, David J A

    2004-11-01

    Over the past two decades, cholesterol-lowering drugs have proven to be effective and have been found to significantly reduce the risk of coronary heart disease (CHD). However, diet and lifestyle factors are still recognized as the first line of intervention for CHD risk reduction by the National Cholesterol Education Program and the American Heart Association, which now advocate use of viscous fibers and plant sterols, and soy protein and nuts, respectively. In a series of metabolically controlled studies, we have combined these four cholesterol-lowering dietary components in the same diet (ie, a dietary portfolio of cholesterol-lowering foods) in an attempt to maximize low-density lipoprotein cholesterol reduction. We have found that the portfolio diet reduced low-density lipoprotein cholesterol by approximately 30% and produced clinically significant reductions in CHD risk. These reductions were the same as found with a starting dose of a first-generation statin drug.

  11. Functionalizing low-density lipoprotein nanoparticles for in vivo near-infrared optical imaging of cancer

    NASA Astrophysics Data System (ADS)

    Corbin, Ian R.; Chen, Juan; Li, Hui; Cao, Weiguo; Zheng, Gang

    2007-07-01

    Low density lipoproteins (LDL) have long been recognized as a potential delivery system for exogenous agents. Imaging agents or drugs can be attached to LDL through surface loading, protein loading or core loading methods. The LDL delivery system has received considerable attention particularly among cancer biologists as it was observed that numerous cancers over-express the low density lipoprotein receptor (LDLR). In this paper we investigate the utility of LDL to transport optical imaging contrast agents for caner detection. The method of loading fluorophores into the core of LDL is attractive as it behaves like an activatable contrast agent. Surface and protein labeled methods also prove to be effective strategies for tracing LDL nanoparticle activity. The strengths and limitations of the LDL carrier system are discussed and novel approaches for imaging cancer with LDL nanoparticles are highlighted.

  12. Dietary fish oil stimulates hepatic low density lipoprotein transport in the rat.

    PubMed Central

    Ventura, M A; Woollett, L A; Spady, D K

    1989-01-01

    These studies were undertaken to examine the effect of fish oil, safflower oil, and hydrogenated coconut oil on the major processes that determine the concentration of low density lipoprotein (LDL) in plasma, i.e., the rate of LDL production and the rates of receptor-dependent and receptor-independent LDL uptake in the various organs of the body. When fed at the 20% level, fish oil reduced plasma LDL-cholesterol levels by 38% primarily by increasing LDL receptor activity in the liver. Dietary safflower oil also increased hepatic LDL receptor activity; however, since the rate of LDL production also increased, plasma LDL-cholesterol levels remained essentially unchanged. Hydrogenated coconut oil had no effect on LDL receptor activity but increased the rate of LDL-cholesterol production causing plasma LDL-cholesterol levels to increase 46%. Dietary fish oil had no effect on the receptor-dependent transport of asialofetuin by the liver, suggesting that the effect of fish oil on hepatic LDL receptor activity was specific and not due to a generalized alteration in the physical properties of hepatic membranes. Finally, dietary fish oil increased hepatic cholesteryl ester levels and suppressed hepatic cholesterol synthesis rates, suggesting that the up-regulation of hepatic LDL receptor activity in these animals was not simply a response to diminished cholesterol availability in the liver. PMID:2760200

  13. [Interaction of very low density lipoproteins (VLDL) with macrophages and their triboluminescence in hypercholesterolemia].

    PubMed

    Voziian, P A; Orel, V E; Baraboĭ, V A; Korniets, G V; Kholodova, Iu D

    1991-01-01

    Accumulation of cholesterol esters and triglycerides in peritoneal mice macrophages in the course of their interaction with lipoproteins of very low density (VLDL) is shown to grow considerably under conditions of hypercholesterolemia. A decrease of triboluminescence intensity characterizing the surface charge has been revealed at hypercholesterolemia both in VLDL and in the blood plasma. It is supposed that the triboluminescence method may be used for testing of the atherosclerotic process development.

  14. The Effects of Low Density Lipoproteins on Endothelial Mediated Vasoactivity in the Coronary Circulation in Swine

    DTIC Science & Technology

    1998-03-27

    low density lipoproteins ( LDL ), alters normal endothelial function in patients with atherosclerosis. The aim of this study was to investigate the...coronary artery. Significance was set at the pS;O.05 level. LDL cholesterol was significantly higher in the high cholesterol (1 16±23 mg/dl) and high...linear relationship was found between the LDL concentration and diastolic blood pressure. Acetylcholine, substance P, adenosine, and nitroglycerin

  15. Low-density lipoprotein cholesterol level and statin use among Medicare beneficiaries with diabetes mellitus.

    PubMed

    Qualls, Laura G; Hammill, Bradley G; Maciejewski, Matthew L; Curtis, Lesley H; Jones, W Schuyler

    2016-05-01

    At the time of this study, guidelines recommended a primary goal of low-density lipoprotein cholesterol level less than 100 mg/dL for all patients, an optional goal of low-density lipoprotein cholesterol less than 70 mg/dL for patients with overt cardiovascular disease and statins for patients with diabetes and overt cardiovascular disease and patients 40 years and older with diabetes and at least one risk factor for cardiovascular disease. This study examined statin use and achievement of lipid goals among 111,730 Medicare fee-for-service beneficiaries 65 years and older in 2011. Three-quarters of patients met the low-density lipoprotein cholesterol goal of less than 100 mg/dL. Patients with cardiovascular disease were more likely to meet the goal than those without, not controlling for other differences. Patients on a statin were more likely to meet the goal. There is considerable opportunity for improvement in cholesterol management in high-risk patients with diabetes mellitus. © The Author(s) 2016.

  16. Lipolytic degradation of human very low density lipoproteins by human milk lipoprotein lipase: the identification of lipoprotein B as the main lipoprotein degradation product.

    PubMed

    Alaupovic, P; Wang, C S; McConathy, W J; Weiser, D; Downs, D

    1986-01-01

    Although the direct conversion of very low density lipoproteins (VLDL) into low density (LDL) and high density (HDL) lipoproteins only requires lipoprotein lipase (LPL) as a catalyst and albumin as the fatty acid acceptor, the in vitro-formed LDL and HDL differ chemically from their native counterparts. To investigate the reason(s) for these differences, VLDL were treated with human milk LPL in the presence of albumin, and the LPL-generated LDL1-, LDL2-, and HDL-like particles were characterized by lipid and apolipoprotein composition. Results showed that the removal of apolipoproteins B, C, and E from VLDL was proportional to the degree of triglyceride hydrolysis with LDL2 particles as the major and LDL1 and HDL + VHDL particles as the minor products of a complete in vitro lipolysis of VLDL. In comparison with native counterparts, the in vitro-formed LDL2 and HDL + VHDL were characterized by lower levels of triglyceride and cholesterol ester and higher levels of free cholesterol and lipid phosphorus. The characterization of lipoprotein particles present in the in vitro-produced LDL2 showed that, as in plasma LDL2, lipoprotein B (LP-B) was the major apolipoprotein B-containing lipoprotein accounting for over 90% of the total apolipoprotein B. Other, minor species of apolipoprotein B-containing lipoproteins included LP-B:C-I:E and LP-B:C-I:C-II:C-III. The lipid composition of in vitro-formed LP-B closely resembled that of plasma LP-B. The major parts of apolipoproteins C and E present in VLDL were released to HDL + VHDL as simple, cholesterol/phospholipid-rich lipoproteins including LP-C-I, LP-C-II, LP-C-III, and LP-E. However, some of these same simple lipoprotein particles were present after ultracentrifugation in the LDL2 density segment because of their hydrated density and/or because they formed, in the absence of naturally occurring acceptors (LP-A-I:A-II), weak associations with LP-B. Thus, the presence of varying amounts of these cholesterol

  17. Softness of atherogenic lipoproteins: a comparison of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) using elastic incoherent neutron scattering (EINS).

    PubMed

    Mikl, Christian; Peters, Judith; Trapp, Marcus; Kornmueller, Karin; Schneider, Wolfgang J; Prassl, Ruth

    2011-08-31

    Apolipoprotein B100 (apoB100)-containing plasma lipoproteins (LDL and VLDL) supply tissues and cells with cholesterol and fat. During lipolytic conversion from VLDL to LDL the size and chemical composition of the particles change, but the apoB100 molecule remains bound to the lipids and regulates the receptor mediated uptake. The molecular physical parameters which control lipoprotein remodeling and enable particle stabilization by apoB100 are largely unknown. Here, we have compared the molecular dynamics and elasticities of VLDL and LDL derived by elastic neutron scattering temperature scans. We have determined thermal motions, dynamical transitions, and molecular fluctuations, which reflect the temperature-dependent motional coupling between lipid and protein. Our results revealed that lipoprotein particles are extremely soft and flexible. We found substantial differences in the molecular resiliences of lipoproteins, especially at higher temperatures. These discrepancies not only can be explained in terms of lipid composition and mobility but also suggest that apoB100 displays different dynamics dependent on the lipoprotein it is bound to. Hence, we suppose that the inherent conformational flexibility of apoB100 permits particle stabilization upon lipid exchange, whereas the dynamic coupling between protein and lipids might be a key determinant for lipoprotein conversion and atherogenicity.

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

    PubMed

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

    2014-01-01

    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; I(2) = 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.

  19. Lipopolysaccharide enhances oxidative modification of low density lipoprotein by copper ions, endothelial and smooth muscle cells.

    PubMed

    Maziere, C; Conte, M A; Dantin, F; Maziere, J C

    1999-03-01

    The effect of lipopolysaccharide (LPS, endotoxin) on low density lipoprotein (LDL) oxidative modification by copper ions, endothelial and smooth muscle cells was studied by determination of the level of lipid peroxidation products (thiobarbituric acid reactive substances or TBARS), the diene level and the electrophoretic mobility of the LDL particle. LPS 25-75 microg/ml induced a dose-dependent increase in LDL oxidation by copper ions, endothelial and smooth muscle cells. At 75 microg LPS/ml, the TBARS content was 1.9, 1.6, and 1.8-fold increased, respectively. The LDL degradation by J774 macrophage-like cells was concomitantly stimulated. Preincubation of the LDL particle with LPS induced a marked increase in the subsequent LDL oxidative modification either by copper ions or by endothelial and smooth muscle cells. In addition, pretreatment of endothelial and smooth muscle cells with LPS also induced an enhancement of LDL oxidative modification performed in the absence of LPS. This effect was accompanied by a parallel increase in superoxide anion release by the cells. These results point at one of the mechanisms involved in the described association between bacterial infection and acute myocardial infarction as well as coronary heart disease.

  20. Studies on the Structure of Low Density Lipoproteins Isolated from Macaca Fascicularis Fed an Atherogenic Diet

    PubMed Central

    Tall, Alan R.; Small, Donald M.; Atkinson, David; Rudel, Lawrence L.

    1978-01-01

    Cynomolgus monkeys, Macaca fascicularis, fed cholesterol-containing saturated-fat diets develop increased levels of high molecular weight plasma low density lipoproteins (LDL), associated with accelerated atherosclerosis. To study the composition and structure of these abnormal particles, LDL from monkeys, fed atherogenic and control diets, were characterized chemically and examined by differential scanning calorimetry and low-angle X-ray scattering. LDL from animals on the experimental diet showed an increase in molecular weight (4.0 to 7.0 × 106, experimental diet compared with 3.0 to 3.7 × 106, control diet) associated with a large increase in cholesterol ester content and concomitant smaller increases in protein, phospholipid, and free cholesterol. There was a strong positive correlation between molecular weight and the number of saturated and monounsaturated cholesterol esters in the particle. In contrast, particle content of polyunsaturated cholesterol esters remained constant despite large changes in total particle cholesterol esters. When examined by calorimetry and X-ray scattering, LDL from monkeys on both diets diplayed a reversible transition of cholesterol esters from an ordered smeticlike (layered) structure to a more disordered state. For all animals on the experimental diet, the peak temperature of the cholesterol-ester transition (42-48°C) was above body temperature (39°C), but below body temperature on the control diet (34-38.5°C). In the experimental group, the transition temperature was correlated with the LDL molecular weight. However, after thermal disruption of LDL, liquid-crystalline transitions of LDL cholesterol esters were observed in the same temperature range as in the intact lipoprotein, which shows that changes in particle size had little effect on the cholesterol-ester transition temperature. Rather, the transition temperature was determined by the degree of saturation of the LDL cholesterol ester fatty acids and the LDL

  1. Effect of cocoa bran on low-density lipoprotein oxidation and fecal bulking.

    PubMed

    Jenkins, D J; Kendall, C W; Vuksan, V; Vidgen, E; Wong, E; Augustin, L S; Fulgoni, V

    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 fecal bulk. Twenty-five healthy normolipidemic subjects (13 men and 12 women) (mean +/- SEM age, 37 +/- 2 years; mean +/- SEM body mass index [calculated as weight in kilograms divided by the square of height in meters], 24.6 +/- 0.7) ate cocoa-bran and chocolate-flavored low-fiber breakfast cereals for 2-week periods, with 2-week washout, in a double-blind crossover study. The cocoa-bran cereal provided 25.0 g/d of total dietary fiber (TDF). The low-fiber cereal (5.6 g/d TDF) was of similar appearance and energy value. Fasting blood samples were obtained at the start and end of each period, and 4-day fecal collections were made from days 11 through 14. High-density lipoprotein (HDL) cholesterol level was higher (7.6% +/- 2.9%; P =.02) and the LDL/HDL cholesterol ratio was lower (6.7% +/- 2.3%; P =.007) for cocoa-bran compared with low-fiber cereal at 2 weeks. No effect was seen on LDL cholesterol oxidation. Mean fecal output was significantly higher for cocoa-bran than for low-fiber cereal (56 +/- 14 g/d; P<.001) and equal to the increase seen in the same subjects with wheat fiber in a previous study. A chocolate-flavored cocoa-bran cereal increased fecal bulk similarly to wheat bran and was associated with a reduction in the LDL/HDL cholesterol ratio. In view of the low-fat, high-fiber nature of the material, these results suggest a possible role for this novel fiber source in the diets of normal, hyperlipidemic, and constipated subjects.

  2. Apple juice consumption reduces plasma low-density lipoprotein oxidation in healthy men and women.

    PubMed

    Hyson, D; Studebaker-Hallman, D; Davis, P A; Gershwin, M E

    2000-01-01

    ABSTRACT Epidemiological studies show that consumption of fruits and vegetables is associated with beneficial effects on human health including reduced risk of coronary artery disease (CAD). Fruits and their juices contain phytochemicals that inhibit in vitro low-density lipoprotein (LDL) oxidation and may account, in part, for their protective effect. However, reports of in vivo antioxidant effects from fruit intake are limited. We conducted a human trial to examine the in vivo effect of consumption of apples (both whole and juice) in an unblinded, randomized, crossover design. Healthy men and women added 375 ml of unsupplemented apple juice or 340 g of cored whole apple to their daily diet for 6 weeks, then crossed over to the alternate product for 6 weeks. Blood samples were obtained at baseline and after each dietary period. Compliance was monitored via biweekly 5-day food records, bodyweight checks, and meetings with study personnel. There were no significant differences between groups in intake of dietary fat, cholesterol, total carbohydrate, sugar, or calories throughout the study. Dietary fiber intake increased by 22% with whole apple consumption. Body weight, fasting serum lipid concentration, and other lipoprotein parameters were unchanged. Apple juice consumption increased ex vivo copper (Cu(++))-mediated LDL oxidation lag time by 20% compared with baseline. Apples and apple juice both reduced conjugated diene formation. Moderate apple juice consumption provides in vivo antioxidant activity. In view of the current understanding of CAD, the observed effect on LDL might be associated with reduced CAD risk and supports the inclusion of apple juice in a healthy human diet.

  3. Oxidized low density lipoprotein (LDL) affects hyaluronan synthesis in human aortic smooth muscle cells.

    PubMed

    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

    2013-10-11

    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 μg/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 μg/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 μg/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.

  4. 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

    Burchardt, Paweł; Zurawski, Jakub; Zuchowski, Bartosz; Kubacki, Tomasz; Murawa, Dawid; Wiktorowicz, Krzysztof; Wysocki, Henryk

    2013-02-21

    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.

  5. Protein components of very low density lipoproteins from hen's egg yolk.

    PubMed

    Bengtsson, G; Marklung, S E; Olivecrona, T

    1977-09-15

    Egg yolk lipoproteins of very low density were found to contain proteins with cofactor activity for lipoprotein lipase. When delipidated very low density lipoproteins were dissolved in 10 mM HCl and fractionated by gel filtration about two thirds of the protein were in several components with estimated molecular weights of 60000 to more than 170000. The major low-molecular-weight proteins were the dimeric and monomeric forms of a previously characterized 9000-dalton peptide. The cofactor activity was not associated with any of these major proteins. A large-scale fractionation method was developed by which two proteins fractions with cofactor activity for lipoprotein lipase were purified more than thousand-fold. One fraction had a molecular size of about 9000 daltons and the other had a size of about 5000 daltons. Both these fractions could be further separated on the basis of charge into several fractions with cofactor activity. The cofactor proteins were relatively soluble both at high and at low pH. The retained their cofactor activity after denaturation in guanidinium hydrochloride and after reduction. During the initial steps in the purification of the cofactor proteins another low-molecular-weight protein followed the cofactors. It had a single 17500-dalton peptide chain and was present in four variants, three of which contained carbohydrate.

  6. Macrophage uptake of low-density lipoprotein modified by 4-hydroxynonenal. An ultrastructural study

    SciTech Connect

    Hoff, H.F.; Cole, T.B. )

    1991-02-01

    We have documented the ultrastructural characteristics of the uptake and processing by mouse peritoneal macrophages (MPM) of low-density lipoprotein (LDL) modified with 4-hydroxynonenal (HNE), an intermediate of lipid peroxidation. This was performed as part of a larger biochemical study assessing the role of LDL oxidation in lipid loading of macrophages during atherogenesis. Gold-labeled LDL that was modified with HNE leading to particle aggregation represented the morphologic probe used. When incubated with MPM, the probe became associated with short segments of cell membrane, probably derived from blebs or from lysed cells. At 37 degrees C there was a time-dependent increase in uptake by MPM, and at 4 hours the increase paralleled the degradation by MPM of 125I-labeled HNE-LDL-cAu. Clathrin-coated pits on the cell surface were consistently associated with probe. Uptake of probe appeared to occur via phagocytosis, because pseudopods frequently surrounded probe, and cytochalasin D quantitatively prevented probe uptake. A time-dependent increase was found in the number of gold particles per unit area within vacuoles, some of which were secondary lysosomes, based on acid phosphatase-positive staining. Thus, HNE-induced aggregation of LDL during oxidation, binding of aggregates to clathrin-coated pits on MPM, and subsequent phagocytosis may represent one of the ways lipid-laden foam cells are formed in vivo.

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

    PubMed

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

    2004-12-01

    The nonlinear optical response of human normal and oxidized by Cu2+ low-density lipoproteins particles (LDL), were investigated by the Z-scan technique as a function of temperature and concentration of LDL particles. The Z-scan signals increase linearly with concentration of normal LDL particles, following the usual Beer-Lambert law in a broad range of concentrations. The oxidized LDL particles do not show nonlinear optical response. On the other hand, normal LDL increases its nonlinear optical response as a function of temperature. These behaviors can be attributed to an absorbing element that is modified by the oxidative process. Contrarily, changes in the physical state of the cores and conformation of the ApoB100 protein due to an increase in temperature seems to enhance their nonlinear optical properties. This tendency is not due to aggregation of particles. The main contribution to the nonlinear optical response of normal LDL particles comes from the phospholipid fraction of the particles.

  8. Giardia lamblia low-density lipoprotein receptor-related protein is involved in selective lipoprotein endocytosis and parasite replication.

    PubMed

    Rivero, Maria R; Miras, Silvana L; Quiroga, Rodrigo; Rópolo, Andrea S; Touz, Maria C

    2011-03-01

    As Giardia lamblia is unable to synthesize cholesterol de novo, this steroid might be obtained from the host's intestinal milieu by endocytosis of lipoproteins. In this work, we identified a putative Giardia lamblia low-density lipoprotein receptor-related proteins (GlLRP), a type I membrane protein, which shares the substrate N-terminal binding domain and a FXNPXY-type endocytic motif with human LRPs. Expression of tagged GlLRP showed that it was localized predominantly in the endoplasmic reticulum, lysosomal-like peripheral vacuoles and plasma membrane. However, the FXNPXY-deleted GlLRP was retained at the plasma membrane suggesting that it is abnormally transported and processed. The low-density lipoprotein and chylomicrons interacted with GlLRP, with this interaction being necessary for lipoprotein internalization and cell proliferation. Finally, we show that GlLRP binds directly to the medium subunit of Giardia adaptor protein 2, indicating that receptor-mediated internalization occurs through an adaptin mechanism.

  9. Direct effects of fatty meals and adiposity on oxidised low-density lipoprotein.

    PubMed

    Laguna-Camacho, Antonio; Alonso-Barreto, Arely S; Mendieta-Zerón, Hugo

    2015-01-01

    High-fat intake and high adiposity contribute to hyperlipaemia. In a hyperlipaemic state, lipoproteins infiltrate arterial wall where they are modified and cause an immune response characteristic of atherosclerosis. A small fraction of modified lipoproteins including oxidised low-density lipoprotein (ox-LDL) returns to circulation. The present study tracked high-fat meals during four weeks as to find effects of sustained frequency change on adiposity and ox-LDL. The findings indicated that changes in frequency of consumption of high-fat eating episodes correlated directly with changes in adiposity and ox-LDL. Hence the number of fatty meals consumed by people with overweight or obesity in few weeks could affect the atherogenic process.

  10. Laboratory validation of a low density lipoprotein apolipoprotein-B assay.

    PubMed

    Kelsey, David E; Toher, Jessica L; Foster, Michael T; Boulanger, James A; Cervinski, Mark A

    2014-11-01

    Numerous publications have shown strong association between CHD risk and either apolipoprotein B (Apo-B) or low density lipoprotein (LDL) particle number (LDL-P). It is however unknown if Apo-B or LDL-P has a stronger predictive ability for future CHD. This uncertainty may be due to the inability of current Apo-B assays to separate the contribution of very low-density lipoprotein particles from the total Apo-B concentration. As such we have performed a laboratory validation of the Maine Standards LDL Apo-B assay on the Roche Cobas 6000 analyzer. Imprecision, linear range, and limit of quantitation studies were performed using quality control materials. Plasma samples collected for lipid profile analysis were analyzed via the LDL Apo-B assay and compared to the LDL cholesterol (LDL-C) concentration determined via direct LDL assay and Friedewald equation. The LDL Apo-B within-run imprecision was 2.3% at 62 mg/dL and 2.2% at 109 mg/dL. The within-laboratory imprecision was 9.7% at 57 mg/dl and 6.1% at 104 mg/dL. Linear regression analysis of LDL Apo-B versus calculated and measured LDL-c resulted in equations of LDL Apo-B=0.620∗(LDL)+45.4, R=0.9063 and LDL-Apo-B=0.607∗(LDL)+38.8, R=0.9393, respectively. Bias plot analyses revealed that at low LDL-C concentration, there was a tendency for a higher than anticipated LDL Apo-B concentration. The Maine Standards LDL Apo-B assay is a precise automated assay and comparison of LDL Apo-B to LDL-c concentration demonstrates that low LDL-C concentrations may still carry residual risk of CHD due to increased concentration of small dense LDL particles. Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  11. Low-Density Lipoprotein Receptor Signaling Mediates the Triglyceride-Lowering Action of Akkermansia muciniphila in Genetic-Induced Hyperlipidemia.

    PubMed

    Shen, Jing; Tong, Xuedong; Sud, Neetu; Khound, Rituraj; Song, Yongyan; Maldonado-Gomez, Maria X; Walter, Jens; Su, Qiaozhu

    2016-07-01

    Akkermansia muciniphila (A muciniphila) is a mucin-degrading bacterium that resides in the mucus layer whose abundance inversely correlates with body weight and the development of diabetes mellitus in mice and humans. The objective of this study was to explore the regulatory effect of A muciniphila on host lipoprotein metabolism, insulin sensitivity, and hepatic metabolic inflammation. By establishing a novel mouse model that colonized the A muciniphila in the gastrointestinal tract of the cAMP-responsive binding protein H (CREBH)-deficient mouse and in vivo chylomicron assay, we found that increased colonization of A muciniphila in the gastrointestinal tract of wild-type mice protected mice from an acute fat load-induced hyperlipidemia compared with vehicle-treated mice. A muciniphila administration also significantly ameliorated chronic hypertriglyceridemia, improved insulin sensitivity, and prevented overproduction of postprandial chylomicrons in CREBH-null mice. Mechanistic studies revealed that increased A muciniphila colonization induced expression of low-density lipoprotein receptors and apolipoprotein E in the hepatocytes of CREBH-null mice, which facilitated the uptake of intermediate-density lipoprotein via the mediation of apolipoprotein B100 and apolipoprotein E, leading to the increased clearance of triglyceride-rich lipoprotein remnants, chylomicron remnants, and intermediate-density lipoproteins, from the circulation. Treatment with A muciniphila further improved hepatic endoplasmic reticulum stress and metabolic inflammation in CREBH-null mice. Increased colonization of the disease-protective gut bacteria A muciniphila protected the host from acute and chronic hyperlipidemia by enhancing the low-density lipoprotein receptor expression and alleviating hepatic endoplasmic reticulum stress and the inflammatory response in CREBH-null mice. © 2016 American Heart Association, Inc.

  12. Transport of beta-very low density lipoproteins and chylomicron remnants by macrophages is mediated by the low density lipoprotein receptor pathway.

    PubMed

    Ellsworth, J L; Kraemer, F B; Cooper, A D

    1987-02-15

    The receptor-mediated uptake of rat hypercholesterolemic very low density lipoproteins (beta VLDL) and rat chylomicron remnants was studied in monolayer cultures of the J774 and P388D1 macrophage cell lines and in primary cultures of mouse peritoneal macrophages. Uptake of 125I-beta VLDL and 125I-chylomicron remnants was reduced 80-90% in the presence of high concentrations of unlabeled human low density lipoproteins (LDL). Human acetyl-LDL did not significantly compete at any concentration tested. Uptake of 125I-beta VLDL and 125I-chylomicron remnants was also competitively inhibited by specific polyclonal antibodies directed against the estrogen-induced LDL receptor of rat liver. Incubation in the presence of anti-LDL receptor IgG, but not nonimmune IgG, reduced specific uptake greater than 80%. Anti-LDL receptor IgG, 125I-beta VLDL, and 125I-chylomicron remnants bound to two protein components of apparent molecular weights 125,000 and 111,000 on nitrocellulose blots of detergent-solubilized macrophage membranes. Between 70-90% of 125I-lipoprotein binding was confined to the 125,000-Da peptide. Binding of 125I-beta VLDL and 125I-chylomicron remnants to these proteins was competitively inhibited by anti-LDL receptor antibodies. Comparison of anti-LDL receptor IgG immunoblot profiles of detergent-solubilized membranes from mouse macrophages, fibroblasts, and liver, and normal and estrogen-induced rat liver demonstrated that the immunoreactive LDL receptor of mouse cells is of a lower molecular weight than that of rat liver. Incubation of J774 cells with 1.0 micrograms of 25-hydroxycholesterol/ml plus 20 micrograms of cholesterol/ml for 48 h decreased 125I-beta VLDL uptake and immuno- and ligand blotting to the 125,000- and 111,000-Da peptides by only 25%. Taken together, these data demonstrate that uptake of beta VLDL and chylomicron remnants by macrophages is mediated by an LDL receptor that is immunologically related to the LDL receptor of rat liver.

  13. Effects of exposure to carbon disulphide on low density lipoprotein cholesterol concentration and diastolic blood pressure.

    PubMed Central

    Egeland, G M; Burkhart, G A; Schnorr, T M; Hornung, R W; Fajen, J M; Lee, S T

    1992-01-01

    The relation of carbon disulphide (CS2) exposure to risk factors for ischaemic heart disease was recently examined using data from a 1979 cross sectional study of 410 male textile workers, of whom 165 were exposed and 245 were unexposed to CS2. Average eight hour CS2 exposure concentrations ranged from 0.6 to 11.8 ppm by job title category among the exposed workers. A significant and positive linear trend in low density lipoprotein cholesterol concentration (LDLc) and diastolic blood pressure with increasing CS2 exposure was found after adjustment for potential confounders. When exposure was examined as a categorical variable (none, low, moderate, and high), the high exposure group had an adjusted mean LDLc that was 0.32 mmol/l greater than the non-exposed group (p = 0.02), and an adjusted mean diastolic blood pressure that was 3.16 mm Hg greater than the non-exposed group (p = 0.09). The effect of CS2 on diastolic blood pressure was strengthened in analyses limited to exposed workers: the high exposure group had an adjusted mean diastolic blood pressure that was 5 mm Hg greater than that of the low exposed group (p = 0.03). Triglyceride, high density lipoprotein cholesterol, and fasting glucose concentration, and systolic blood pressure were not affected by exposure. Blood lead concentration was positively associated with systolic and diastolic blood pressure. The results indicate that relatively modest exposure to CS2 may raise LDLc concentration and diastolic blood pressure and suggest mechanisms by which exposure to CS2 may influence risk of ischaemic heart disease. Also the results provide further support for the hypothesis of a possible association between blood lead concentration and blood pressure. PMID:1571299

  14. Low Density Lipoprotein Receptor-Related Protein and Apolipoprotein E Expression is Altered in Schizophrenia

    PubMed Central

    Gibbons, Andrew Stuart; Thomas, Elizabeth A.; Scarr, Elizabeth; Dean, Brian

    2010-01-01

    Our recent microarray study reported altered mRNA expression of several low density lipoprotein receptor-related proteins (LRP) associated with the first 4 years following diagnosis with schizophrenia. Whilst this finding is novel, apolipoprotein E (APOE), which mediates its activity through LRPs, has been reported by several studies to be altered in brains of subjects with schizophrenia. We used qPCR to measure the expression of LRP2, LRP4, LRP6, LRP8, LRP10 and LRP12 mRNA in Brodmann's area (BA) 46 of the dorsolateral prefrontal cortex in 15 subjects with short duration of illness schizophrenia (SDS) and 15 pair matched controls. We also used Western blotting to measure APOE protein expression in BA46 from these subjects. Amongst the LRPs examined, LRP10 expression was significantly increased (P = 0.03) and LRP12 was significantly decreased (P < 0.01) in SDS. APOE protein expression was also increased in SDS (P = 0.01). No other marker examined in this study was altered with diagnosis. Our data supports a role for distinct members of the LRP family in the pathology of schizophrenia and adds weight to the hypothesis that aberrant apolipoprotein signaling is involved in the early stages of schizophrenia. PMID:21423430

  15. Oxidized low-density lipoproteins upregulate proline oxidase to initiate ROS-dependent autophagy.

    PubMed

    Zabirnyk, Olga; Liu, Wei; Khalil, Shadi; Sharma, Anit; Phang, James M

    2010-03-01

    Epidemiological studies showed that high levels of oxidized low-density lipoproteins (oxLDLs) are associated with increased cancer risk. We examined the direct effect of physiologic concentrations oxLDL on cancer cells. OxLDLs were cytotoxic and activate both apoptosis and autophagy. OxLDLs have ligands for peroxisome proliferator-activated receptor gamma and upregulated proline oxidase (POX) through this nuclear receptor. We identified 7-ketocholesterol (7KC) as a main component responsible for the latter. To elucidate the role of POX in oxLDL-mediated cytotoxicity, we knocked down POX via small interfering RNA and found that this (i) further reduced viability of cancer cells treated with oxLDL; (ii) decreased oxLDL-associated reactive oxygen species generation; (iii) decreased autophagy measured via beclin-1 protein level and light-chain 3 protein (LC3)-I into LC3-II conversion. Using POX-expressing cell model, we established that single POX overexpression was sufficient to activate autophagy. Thus, it led to autophagosomes accumulation and increased conversion of LC3-I into LC3-II. Moreover, beclin-1 gene expression was directly dependent on POX catalytic activity, namely the generation of POX-dependent superoxide. We conclude that POX is critical in the cellular response to the noxious effects of oxLDL by activating protective autophagy.

  16. Low-density lipoprotein transport in blood vessel walls of squirrel monkeys

    SciTech Connect

    Tompkins, R.G.; Yarmush, M.L.; Schnitzer, J.J.; Colton, C.K.; Smith, K.A.; Stemerman, M.B. )

    1989-08-01

    Transmural accumulations of low-density lipoprotein (LDL) were examined in the blood vessel walls of four squirrel monkeys. Vascular wall concentrations of LDL were measured using quantitative autoradiography after {sup 125}I-labeled LDL circulation for 30 min. Profiles of relative tissue concentration from different sections in the same region were similar to each other, and there was little animal-to-animal variation. Concentrations were highest near the luminal endothelium, lower near the medial-adventitial border, and lowest within the media. Profiles from different regions fell into three groups: (1) aortic samples had steep intimal concentration gradients and near-zero media concentrations; (2) the iliac, femoral, popliteal, and common carotid arteries had higher intimal concentrations than group 1 but had similar concentrations deep within the media; and (3) the cerebral and coronary arteries, inferior vena cava, and pulmonary artery had intimal concentrations that were similar to group 2, but the concentrations deep within the media were greater than either groups 1 or 2. Arterial bifurcation profiles from the inner wall and the outer walls were similar to each other and to profiles from the upstream and downstream areas. Out of 280 total sites examined, 15 examples of profiles with substantially increased concentrations near the luminal endothelium were found scattered throughout the cardiovascular system, demonstrating that there are focal regions throughout the cardiovascular system which have greatly increased {sup 125}I-LDL transendothelial permeability.

  17. Ferritin protects endothelial cells from oxidized low density lipoprotein in vitro.

    PubMed Central

    Juckett, M. B.; Balla, J.; Balla, G.; Jessurun, J.; Jacob, H. S.; Vercellotti, G. M.

    1995-01-01

    Low density lipoprotein (LDL), if it becomes oxidized, develops several unique properties including the capacity to provoke endothelial cytotoxicity via metal-catalyzed free radical-mediated mechanisms. As were previously have shown that iron-catalyzed oxidant injury to endothelial cells can be attenuated by the addition of exogenous iron chelators such as the lazaroids and deferoxamine, we have examined whether the endogenous iron chelator, ferritin, might provide protection from oxidized LDL. LDL oxidized by iron-containing hemin and H2O2 is toxic to endothelial cells in a time- and dose-dependent fashion. Endothelial cell ferritin content is increased by pretreatment of cells with iron compounds or by the direct addition of exogenous apoferritin; ferritin-loaded cells are markedly resistant to the toxicity caused by oxidized LDL. Iron inactivation by ferritin depends on its ferroxidase activity. When a recombinant human ferritin heavy chain mutant, 222, which is devoid of ferroxidase activity, is added to endothelial cells, unlike the excellent protection afforded by the wild-type recombinant heavy chain, endothelial cells are not protected from oxidized LDL. To assess the in vivo relevance of our observation, we examined human coronary arteries of cardiac explants taken from patients with end-stage atherosclerosis. Large amounts of immunoreactive ferritin are focally detected in atherosclerotic lesions, specifically in the myofibroblasts, macrophages, and endothelium without a notable increase in Prussian blue-detectable iron. These findings suggest that ferritin may modulate vascular cell injury in vivo. Images Figure 3 Figure 4 PMID:7677189

  18. Glucose influence on copper ion-dependent oxidation of low density lipoprotein.

    PubMed

    Ghaffari, Mohammad Ali; Mojab, Samad

    2009-01-01

    It is well established that oxidative modification of low density lipoprotein (LDL) plays a causal role in human atherogenesis and the risk of atherosclerosis is increased in patients with diabetes mellitus. We examined the in vitro effect of glucose on native and glycated LDL oxidation using copper ion dependent oxidation system. In this study, LDL was isolated from plasma by ultracentrifugation using a single step discontinuous gradient. Native LDL preparations were glycated by glucose and also were oxidized by copper ions. LDL glycation and oxidation levels were estimated by sodium periodate assay and thiobarbituric acid reactive substances (TBARS), respectively. Then, native LDL was incubated with glucose and copper and LDL oxidation was estimated by TBARS. Finally, oxidation of glycated LDL was studied in presence of copper ions by TBARS and relative electrophoretic mobility on polyacrylamide gel. This study showed that glucose considerably decreased the oxidation of native LDL by copper ions. But oxidation of glycated LDL elevated with presence of copper ions. The results of this investigation show that LDL glycated in vitro is prone to oxidation by copper ions. Thus, promotion of glycated LDL oxidation by glucose is specific for copper ion dependent oxidation and involves increased copper ion reduction. These results provide one mechanism that may enhanced LDL oxidation in diabetes and thus contribute to the pathogenesis of atherosclerosis in diabetic patients.

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

    PubMed Central

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

    2014-01-01

    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

  20. Native low density lipoprotein induces pancreatic β cell apoptosis through generating excess reactive oxygen species.

    PubMed

    Lu, Xiuli; Liu, Jianli; Cao, Xiangyu; Hou, Xiao; Wang, Xude; Zhao, Chenguang; Wang, Youliang; Li, Yang; Seo, Hisao; Gao, Bing

    2011-07-26

    The growing evidences demonstrated hyperlipidemia in obesity and type 2 diabetes is characterized by high levels of free fatty acids, low-density lipoprotein (LDL), triglyceride, and cholesterol. We investigated the effect of LDL particles (LDLs) loading on MIN6 cells derived from pancreatic β cells. Exposure of MIN6 cells to LDLs induced apoptosis in dose and time-dependent manner, demonstrated by the TUNEL in situ apoptotic assay. The immunocytochemical analysis and Western blotting revealed that the LDLs-induced apoptosis is associated with the activation of caspase 3 and upregulation of p53. The intracellular concentration of Reactive Oxygen Species (ROS) measured by use of DCFHDA was significantly increased after loading LDLs, demonstrating the induced apoptosis by LDLs loading was mediated through oxidative stress. Addition of reduced form of Glutathione (GSH) in the medium rescued MIN6 cells from apoptosis. The Cellular cholesterol level was increased significantly after LDLs loading, suggesting that the excess cholesterol induced by LDLs loading might contribute to the apoptosis in MIN6s. Agarose electrophoresis demonstrated that the LDLs added to the medium were not oxidized. Taken together, these results demonstrate that the LDLs loading can induce apoptosis of MIN6 cells mediated by the excess cellular cholesterol and generation of oxidative stress.

  1. Effects of lovastatin on hepatic expression of the low-density lipoprotein receptor in nephrotic rats.

    PubMed

    Wei, L X; Chen, L; Wang, W M; Zhang, X H; Wu, J B; Liang, S F; Shu, G Y

    2014-02-19

    To investigate the effect of the HMG-CoA reductase inhibitor lovastatin on the expression of the receptor for hepatic low-density lipoprotein (LDL) in a rat model with kidney disease, and to identify the mechanisms in statin treatment of nephrotic syndrome with hyperlipidemia, a rat model with nephrotic syndrome was established. Thirty male Sprague-Dawley rats were treated with lovastatin for 2 weeks using gavage. The expression of protein and mRNA of the LDL receptor in the rat liver was detected with Western blot and RT-PCR, respectively, and blood-biochemical indices were also recorded for each group. Compared with the untreated control group, lovastatin treatment significantly decreased the levels of serum total cholesterol, LDL cholesterol, triglycerides, and urinary protein. In addition, lovastatin treatment significantly increased the levels of serum albumin and hepatic LDL receptor proteins, but had no effect on the expression of hepatic LDL receptor mRNA. Treatment with lovastatin markedly increased the expression of the hepatic LDL receptor in rats with nephrotic syndrome, which was accompanied by significantly improved hyperlipidemia.

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

    NASA Astrophysics Data System (ADS)

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

    2014-04-01

    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 PPARα'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.

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

    PubMed Central

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

    2014-01-01

    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 PPARα's transcription. The present study demonstrates a lipid disturbance caused by PFOS and thus point to its role in inhibiting the secretion and normal function of low density lipoproteins. PMID:24694979

  4. Red grape seed extract improves lipid profiles and decreases oxidized low-density lipoprotein in patients with mild hyperlipidemia.

    PubMed

    Razavi, Seyed-Mostafa; Gholamin, Sharareh; Eskandari, Ali; Mohsenian, Nakta; Ghorbanihaghjo, Amir; Delazar, Abbas; Rashtchizadeh, Nadereh; Keshtkar-Jahromi, Maryam; Argani, Hassan

    2013-03-01

    Hyperlipidemia can lead to atherosclerosis by lipoprotein deposition inside the vessel wall and oxidative stress induction that leads to the formation of atherosclerotic plaque. Oxidized low-density lipoprotein particles (Ox-LDL) have a key role in the pathogenesis of atherosclerosis. The lipid-lowering properties and antioxidants of the grape seed can be beneficial in atherosclerosis prevention. We conducted a randomized double-blind placebo-controlled crossover clinical trial. Fifty-two mildly hyperlipidemic individuals were divided into two groups that received either 200 mg/day of the red grape seed extract (RGSE) or placebo for 8 weeks. After an 8-week washout period, the groups were crossed over for another 8 weeks. Lipid profiles and Ox-LDL were measured at the beginning and the end of each phase. RGSE consumption reduced total cholesterol (-10.68±26.76 mg/dL, P=.015), LDL cholesterol (-9.66±23.92 mg/dL, P=.014), and Ox-LDL (-5.47±12.12 mg/dL, P=.008). While triglyceride and very low-density lipoprotein cholesterol were decreased and high-density lipoprotein cholesterol was increased by RGSE, the changes were not statistically significant. RGSE consumption decreases Ox-LDL and has beneficial effects on lipid profile-consequently decreasing the risk of atherosclerosis and cardiovascular disorders-in mild hyperlipidemic individuals.

  5. [Effect of metal cations on the copper induced peroxidation of the low density lipoproteins].

    PubMed

    Dremina, E S; Vlasova, I I; Vakhrusheva, T V; Sharov, V S; Azizova, O A

    1997-01-01

    The effect of metal cations on copper-catalyzed lipid peroxidation (LPO) of low density lipoproteins (LDL) was examined. The presence of metal cations in the incubation media containing LDL (0.8 mg protein/ml) and CuSO4 (0-80 microM) influenced on LPO of LDL as evident by the measurement of TBARS. With the concentrations of CuSO4 less than 10 microM, the metal cations caused an increase in LDL peroxidation. Zn2+ appeared to be the most effective inductor, Mn2+ was less effective, and the influence of Ca2+ and Mg2+ was insignificant. With greater CuSO4 concentrations Mg2+ showed no effect on TBARS formation in LDL while the addition of other nontransition metal cations to the incubation mixture led to the inhibition of LDL peroxidation. The capacity for inhibition decreased in the row Mn2+ > Zn2+ > Ca2+ > Mg2+. The possible mechanism explaining these results may be in the competition of metal ions for copper binding sites on LDL. Our results allow to suggest the existence of two types of copper binding sites on LDL, tight-binding sites which are non-effective in LPO and effective weak-binding sites.

  6. Clinical efficacy and safety of evolocumab for low-density lipoprotein cholesterol reduction.

    PubMed

    Henry, Courtney A; Lyon, Ronald A; Ling, Hua

    2016-01-01

    Multiple categories of medications have been developed to manage lipid profiles and reduce the risk of cardiovascular events in patients with heart disease. However, currently marketed medications have not solved the problems associated with preventing and treating cardiovascular diseases completely. A substantial population of patients cannot take advantage of statin therapy due to statin intolerance, heart failure, or kidney hemodialysis, suggesting a need for additional effective agents to reduce low-density lipoprotein cholesterol (LDL-C) levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was discovered in 2003 and subsequently emerged as a novel target for LDL-C-lowering therapy. Evolocumab is a fully human monoclonal immunoglobulin G2 (IgG2) directed against human PCSK9. By inactivating PCSK9, evolocumab upregulates LDL receptors causing increased catabolism of LDL-C and the consequent reduction of LDL-C levels in blood. Overall, evolocumab has had notable efficacy, with LDL-C reduction ranging from 53% to 75% in monotherapy and combination therapies, and is associated with minor adverse effects. However, studies regarding the ability of evolocumab to reduce mortality as well as long-term safety concerns are limited. The fact that the drug was introduced at a cost much higher than the existing medications and shows a low incremental mortality benefit suggests that many payers will consider evolocumab to have an unfavorable cost-benefit ratio.

  7. Protein modification elicited by oxidized low-density lipoprotein (LDL) in endothelial cells: protection by (-)-epicatechin.

    PubMed

    Steffen, Yvonne; Jung, Tobias; Klotz, Lars-Oliver; Schewe, Tankred; Grune, Tilman; Sies, Helmut

    2007-04-01

    The action of oxidatively modified low-density lipoprotein (oxLDL) on vascular endothelial cells has been proposed to be a crucial process leading to endothelial dysfunction and atherogenesis. OxLDL was shown here to elicit oxidative stress in bovine aortic endothelial cells or human umbilical vein endothelial cells, as judged by an increase in 2',7'-dichlorofluorescein fluorescence and elevated levels of carbonylated, nitrated, and 2-hydroxynonenal-coupled proteins. These effects were sensitive to apocynin, indicating involvement of NADPH oxidase. A 170-kDa polypeptide carbonylated upon exposure of cells to oxLDL was identified by immunoprecipitation as EGF receptor. Immunocytochemical visualization by confocal microscopy revealed the highest levels of modified proteins in the perinuclear region. Exposure of endothelial cells to oxLDL led to modulation of the expression levels of *NO synthases; the endothelial isoform (eNOS) was down-regulated via proteasomal degradation, whereas the inducible isoform (iNOS) was up-regulated in an enzymatically active state. eNOS protein was found to be both carbonylated and nitrated upon exposure of cells to oxLDL. iNOS contributed to the generation of modified proteins as judged by the effects of the selective inhibitor L-NIO. These oxLDL-elicited changes in vascular endothelial cells described were suppressed by (-)-epicatechin, a dietary polyphenol, which inhibited NADPH oxidase activity in these cells.

  8. N-acetylcysteine inhibits in vivo oxidation of native low-density lipoprotein

    PubMed Central

    Cui, Yuqi; Narasimhulu, Chandrakala A.; Liu, Lingjuan; Zhang, Qingbin; Liu, Patrick Z.; Li, Xin; Xiao, Yuan; Zhang, Jia; Hao, Hong; Xie, Xiaoyun; He, Guanglong; Cui, Lianqun; Parthasarathy, Sampath; Liu, Zhenguo

    2015-01-01

    Low-density lipoprotein (LDL) is non-atherogenic, while oxidized LDL (ox-LDL) is critical to atherosclerosis. N-acetylcysteine (NAC) has anti-atherosclerotic effect with largely unknown mechanisms. The present study aimed to determine if NAC could attenuate in vivo LDL oxidation and inhibit atherosclerosis. A single dose of human native LDL was injected intravenously into male C57BL/6 mice with and without NAC treatment. Serum human ox-LDL was detected 30 min after injection, reached the peak in 3 hours, and became undetectable in 12 hours. NAC treatment significantly reduced serum ox-LDL level without detectable serum ox-LDL 6 hours after LDL injection. No difference in ox-LDL clearance was observed in NAC-treated animals. NAC treatment also significantly decreased serum ox-LDL level in patients with coronary artery diseases and hyperlipidemia without effect on LDL level. Intracellular and extracellular reactive oxidative species (ROS) production was significantly increased in the animals treated with native LDL, or ox-LDL and in hyperlipidemic LDL receptor knockout (LDLR−/−) mice that was effectively prevented with NAC treatment. NAC also significantly reduced atherosclerotic plaque formation in hyperlipidemic LDLR−/− mice. NAC attenuated in vivo oxidation of native LDL and ROS formation from ox-LDL associated with decreased atherosclerotic plaque formation in hyperlipidemia. PMID:26536834

  9. Edaravone attenuates monocyte adhesion to endothelial cells induced by oxidized low-density lipoprotein

    SciTech Connect

    Li, Zhijuan Cheng, Jianxin; Wang, Liping

    2015-10-30

    Oxidized low-density lipoprotein (oxLDL) plays a vital role in recruitment of monocytes to endothelial cells, which is important during early stages of atherosclerosis development. Edaravone, a potent and novel scavenger of free radicals inhibiting hydroxyl radicals, has been clinically used to reduce the neuronal damage following ischemic stroke. In the present study, Edaravone was revealed to markedly reduce oxLDL-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). The inhibitory mechanism of Edaravone was associated with suppression of the chemokine MCP-1 and adhesion molecule VCAM-1 and ICAM-1 expression. In addition, luciferase reporter assay results revealed that administration of Edaravone attenuated the increase in NF-κB transcriptional activity induced by oxLDL. Notably, it's also shown that Edaravone treatment blocked oxLDL induced p65 nuclear translocation in HUVECs. Results indicate that Edaravone negatively regulates endothelial inflammation. - Highlights: • Edaravone reduces oxLDL-induced monocyte adhesion to HUVECs. • Edaravone attenuates oxLDL-induced expression of MCP-1, VCAM-1, and ICAM-1. • Edaravone reduces NF-κB transcriptional activity and p65 nuclear translocation.

  10. Location and regulation of low-density lipoprotein receptors in intestinal epithelium.

    PubMed

    Fong, L G; Fujishima, S E; Komaromy, M C; Pak, Y K; Ellsworth, J L; Cooper, A D

    1995-07-01

    The expression, distribution, and some aspects of the regulation of low-density lipoprotein (LDL) receptors in rat intestinal epithelial cells were examined. Cells prepared by a perfusion technique provided a pure preparation of epithelial cells and could be manipulated to produce crypt-villus units or villi alone. On a total protein basis, the abundance of LDL receptors in villus cell membranes was half that in hepatic membranes. The level of receptors in both tissues was reduced by feeding an atherogenic diet but was increased only in the liver by ethinyl estradiol-induced hypocholesterolemia. The level of LDL receptor mRNA in intestinal epithelial cells was somewhat lower than in liver. Regulation of LDL receptor mRNA was similar to that of protein. Judged by the ratio of mRNA in villus cells to the villus-crypt unit and nuclear run-on assay for LDL receptor gene transcription, we conclude that LDL receptor mRNA is produced in the villus cells. The effect of fat feeding was regulated at the level of transcription. Expression in villus cells in ileum was severalfold higher than in jejunum and higher than in the liver. Together the results suggest serum cholesterol level is not the prime determinant of LDL receptor level in intestine, but LDL degradation in this organ may be regulated by factors in the lumen.

  11. Oxidized low-density lipoprotein decreases VEGFR2 expression in HUVECs and impairs angiogenesis.

    PubMed

    Zhang, Min; Jiang, Li

    2016-12-01

    Atherosclerosis (AS), which is triggered by endothelial cell injury, evolves into a chronic inflammatory disease. Oxidized low-density lipoprotein (ox-LDL) is an important risk factor for the development of atherosclerosis; ox-LDL induces atherosclerotic plaque formation via scavenging receptors. The present study used ox-LDL-treated human umbilical vein endothelial cells (HUVECs) to investigate the effect of ox-LDL on angiogenesis. ox-LDL decreased HUVEC proliferation by MTT, induced apoptosis by Annexin V-fluorescein isothiocyanate (FITC) staining and markedly suppressed HUVEC tube formation by the Matrigel assay in a dose-dependent manner. Angiogenesis has been correlated with monocyte invasion, plaque instability and atherosclerotic lesion formation. In addition, ox-LDL induced the overproduction of reactive oxygen species using DCFH-DA staining and increased caspase-3 activity. Vascular endothelial growth factor receptor 2 (VEGFR2) were detected by quantitative polymerase chain reaction and western blot analysis and has previously been observed to have a key role in angiogenesis. Furthermore, the present study demonstrated that the abundance of VEGFR2 was decreased in ox-LDL-treated HUVECs. These results suggested that ox-LDL impairs angiogenesis via VEGFR2 degradation, thus suggesting that VEGFR2 may be involved in adaptation to oxidative stress and AS.

  12. Analysis of non-Newtonian effects on Low-Density Lipoprotein accumulation in an artery.

    PubMed

    Iasiello, Marcello; Vafai, Kambiz; Andreozzi, Assunta; Bianco, Nicola

    2016-06-14

    In this work, non-Newtonian effects on Low-Density Lipoprotein (LDL) transport across an artery are analyzed with a multi-layer model. Four rheological models (Carreau, Carreau-Yasuda, power-law and Newtonian) are used for the blood flow through the lumen. For the non-Newtonian cases, the arterial wall is modeled with a generalized momentum equation. Convection-diffusion equation is used for the LDL transport through the lumen, while Staverman-Kedem-Katchalsky, combined with porous media equations, are used for the LDL transport through the wall. Results are presented in terms of filtration velocity, Wall Shear Stresses (WSS) and concentration profiles. It is shown that non-Newtonian effects on mass transport are negligible for a healthy intramural pressure value. Non-Newtonian effects increase slightly with intramural pressure, but Newtonian assumption can still be considered reliable. Effects of arterial size are also analyzed, showing that Newtonian assumption can be considered valid for both medium and large arteries, in predicting LDL deposition. Finally, non-Newtonian effects are also analyzed for an aorta-common iliac bifurcation, showing that Newtonian assumption is valid for mass transport at low Reynolds numbers. At a high Reynolds number, it has been shown that a non-Newtonian fluid model can have more impact due to the presence of flow recirculation.

  13. Alpha-2-macroglobulin gene, oxidized low-density lipoprotein receptor-1 locus, and sporadic Alzheimer's disease.

    PubMed

    Colacicco, Anna Maria; Solfrizzi, Vincenzo; D'Introno, Alessia; Capurso, Cristiano; Kehoe, Patrick G; Seripa, Davide; Pilotto, Alberto; Santamato, Andrea; Capurso, Antonio; Panza, Francesco

    2009-09-01

    A total sample of 169 AD patients, and 264 age- and sex-matched unrelated caregivers from Apulia, southern Italy, were genotypized for alpha-2-macroglobulin (A2M) Val1000/Ile single-nucleotide polymorphism (SNP) (rs669), apolipoprotein E (APOE), and SNPs (+1073 and +1071) in the oxidized low-density lipoprotein receptor-1 (OLR1) gene on chromosome 12. A2M allele and genotype frequencies were similar between AD patients and controls, also after stratification for late onset (>/=70 years) and early onset (<70 years) or APOE varepsilon4 status. However, there was evidence in support of LD between the OLR1+1071, the OLR1+1073, and the rs669 SNPs, with T-C-A haplotype being associated with significant increased risk of AD in both the whole sample and when we stratified according to early and late onset AD subjects, with the allelic association with AD predominantly from the OLR1+1073 SNP, further supporting the role of OLR1 as a candidate risk gene for sporadic AD.

  14. Polymorphisms in the oxidized low-density lipoprotein receptor-1 gene and risk of Alzheimer's disease.

    PubMed

    D'Introno, Alessia; Solfrizzi, Vincenzo; Colacicco, Anna M; Capurso, Cristiano; Torres, Francesco; Capurso, Sabrina A; Capurso, Antonio; Panza, Francesco

    2005-03-01

    The +1073 C/T polymorphism of the oxidized low-density lipoprotein receptor-1 (OLR1) gene has been reported to be associated with late-onset Alzheimer's disease, whereas for the +1071 T/A polymorphism no association was found. We genotyped 169 sporadic Alzheimer's disease patients and 264 sex- and age-matched nondemented controls from Southern Italy for OLR1 +1073 C/T and +1071 T/A polymorphisms and for apolipoprotein E and LBP-1c/CP2/LSF. We also performed haplotype analysis. For the +1073 C/T polymorphism, the C allele and the CC genotype have been associated with a higher risk for Alzheimer's disease without apolipoprotein E or CP2 interaction. The two polymorphisms were in linkage disequilibrium, with the haplotype T-C at significant increased risk of developing Alzheimer's disease in the whole sample and in elderly persons 70 years or older. In our population, the +1073 C/T OLR1 polymorphism exhibited a significant association with Alzheimer's disease, further supporting the role of OLR1 as a candidate risk gene for sporadic Alzheimer's disease.

  15. Oxidized low-density lipoprotein decreases VEGFR2 expression in HUVECs and impairs angiogenesis

    PubMed Central

    Zhang, Min; Jiang, Li

    2016-01-01

    Atherosclerosis (AS), which is triggered by endothelial cell injury, evolves into a chronic inflammatory disease. Oxidized low-density lipoprotein (ox-LDL) is an important risk factor for the development of atherosclerosis; ox-LDL induces atherosclerotic plaque formation via scavenging receptors. The present study used ox-LDL-treated human umbilical vein endothelial cells (HUVECs) to investigate the effect of ox-LDL on angiogenesis. ox-LDL decreased HUVEC proliferation by MTT, induced apoptosis by Annexin V-fluorescein isothiocyanate (FITC) staining and markedly suppressed HUVEC tube formation by the Matrigel assay in a dose-dependent manner. Angiogenesis has been correlated with monocyte invasion, plaque instability and atherosclerotic lesion formation. In addition, ox-LDL induced the overproduction of reactive oxygen species using DCFH-DA staining and increased caspase-3 activity. Vascular endothelial growth factor receptor 2 (VEGFR2) were detected by quantitative polymerase chain reaction and western blot analysis and has previously been observed to have a key role in angiogenesis. Furthermore, the present study demonstrated that the abundance of VEGFR2 was decreased in ox-LDL-treated HUVECs. These results suggested that ox-LDL impairs angiogenesis via VEGFR2 degradation, thus suggesting that VEGFR2 may be involved in adaptation to oxidative stress and AS. PMID:28105106

  16. Low density lipoprotein adsorption on sol-gel derived alumina for blood purification therapy.

    PubMed

    Asano, Takuji; Tsuru, Kanji; Hayakawa, Satoshi; Osaka, Akiyoshi

    2008-01-01

    Among the clinical treatments of Familial Hyper cholesterolemia patients to reduce the concentration of low density lipoprotein (LDL), blood purification therapy is most suitable in which a blood-compatible adsorbent is employed. In the present study, alumina powders were prepared via a sol-gel route to develop a LDL-adsorbent Aluminum tri2-propoxide was hydrolyzed and subsequently calcined up to 1200 degrees C. Surface charge density and pore size distribution were measured, and the phases were identified. The alumina calcined above 400 degrees C had excellent blood compatibility in terms of endogenous clotting parameters, i.e., partial thromboplastin time: (PTT), prothrombin time: (PT), and the amount of fibrinogen: (Fib). The amount of LDL-adsorption (DeltaW(LDL)) increased with the calcining temperature, showing a good linear correlation to surface charge density. The 1200 degrees C sample consisted only of alpha-alumina, and was greatest in DeltaW(LDL). All samples involved pores smaller than 20 nm but not the pores large enough to accommodate LDL molecules (20-25 nm). From those results, it was concluded for the present alumina particles that the surface charge density was the primary factor and that the chemical activity of alpha-alumina also contributed to the excellent LDL-adsorption for the 1200 degrees C sample, while entrapping LDL in the pores was not an active mechanism.

  17. Influence of oxidized low-density lipoproteins (LDL) on the viability of osteoblastic cells.

    PubMed

    Brodeur, Mathieu R; Brissette, Louise; Falstrault, Louise; Ouellet, Pascale; Moreau, Robert

    2008-02-15

    Cardiovascular diseases have recently been noted as potential risk factors for osteoporosis development. Although it is poorly understood how these two pathologies are related, it is a known fact that oxidized low-density lipoproteins (OxLDL) constitute potential determinants for both of them. The current study investigated the metabolism of OxLDL by osteoblasts and its effect on osteoblastic viability. The results obtained show that OxLDL are internalized but not degraded by osteoblasts while they can selectively transfer their CE to these cells. It is also demonstrated that OxLDL induce proliferation at low concentrations but cell death at high concentrations. This reduction of osteoblast viability was associated with lysosomal membrane damage caused by OxLDL as demonstrated by acridine orange relocalization. Accordingly, chloroquine, an inhibitor of lysosomal activity, accentuated cell death induced by OxLDL. Finally, we demonstrate that osteoblasts have the capacity to oxidize LDL and thereby potentially increase the local concentration of OxLDL. Overall, the current study confirms the potential role of OxLDL in the development of osteoporosis given its influence on osteoblastic viability.

  18. Oxidation-labile subfraction of human plasma low density lipoprotein isolated by ion-exchange chromatography.

    PubMed

    Shimano, H; Yamada, N; Ishibashi, S; Mokuno, H; Mori, N; Gotoda, T; Harada, K; Akanuma, Y; Murase, T; Yazaki, Y

    1991-05-01

    We isolated subfractions of human plasma low density lipoprotein (LDL) using ion-exchange chromatography. Plasma LDL from normolipidemic subjects were applied to a DEAE Sepharose 6B column. After elution of the bulk of LDL at 150 mM NaCl (the major fraction), the residual LDL was eluted at 500 mM NaCl and designated as the minor fraction. The minor fraction, only less than 1% of total LDL, tended to be somewhat similar in certain properties to oxidized LDL, e.g., an increased negative charge, higher protein/cholesterol ratio, and a higher flotation density than native LDL. These results were consistent with data reported by Avogaro et al. (1988. Arteriosclerosis. 8: 79-87). However, assays of 125I-labeled LDL binding activity for LDL receptors equal to that of the major fraction. Incorporation of [14C]oleate into cholesteryl ester [acyl-CoA:cholesterol acyltransferase (ACAT) activity] in mouse peritoneal macrophages incubated with the minor fraction was only slightly greater than that with the major fraction. Incubation of the minor fraction with 0.5 microM Cu2+ caused a remarkable stimulation of ACAT activity, while stimulation by the major fraction required incubation with 5 microM Cu2+, suggesting that the minor fraction was relatively labile to oxidation. The minor but definite presence of a plasma LDL subfraction more negative and susceptible to oxidation implicates the possibility of its association with atherogenesis.

  19. Dietary corn fractions reduce atherogenesis in low-density lipoprotein receptor knockout mice.

    PubMed

    Masisi, Kabo; Le, Khuong; Ghazzawi, Nora; Moghadasian, Mohammed H; Beta, Trust

    2017-01-01

    Accumulating evidence has suggested that intake of whole grains is a protective factor against pathogenesis of coronary artery disease. The exact mechanisms, however, are still not clearly understood. In this study, we hypothesized that adequate intake of corn fractions (aleurone, endosperm and germ) can modify lipid profiles in relation to atherosclerotic lesion development in low-density lipoprotein receptor knockout (LDLr-KO) mice. The purpose of the present study was to investigate the potential cardiovascular benefits of corn fractions in LDLr-KO mice through a number of biomarkers including lipid profile, and morphologic and morphometrical analysis of atherosclerotic lesions in aortic root. Four groups of male LDLr-KO mice were fed with the experimental diets supplemented with (3 treated) or without (control) 5% (wt/wt) of each of corn fractions for 10 weeks. All diets were supplemented with 0.06% (wt/wt) cholesterol. Compared with mice in the control group, atherosclerotic lesions in the aortic roots were significantly reduced (P=.003) in the mice that were fed diet supplemented with aleurone and germ fractions. This effect was associated with significant reductions in plasma total (P=.02) and LDL (P=.03) cholesterol levels, and an increase in fecal cholesterol excretion (P=.04). Furthermore, abdominal fat mass was significantly reduced by consumption of aleurone (P=.03). In summary, the consumption of aleurone and germ may help attenuate atherosclerosis by reducing plasma total and LDL cholesterol levels.

  20. Novel low-density lipoprotein (LDL) oxidation model: antioxidant capacity for the inhibition of LDL oxidation.

    PubMed

    Chu, Yi-Fang; Liu, Rui Hai

    2004-11-03

    A novel model of peroxyl radical initiated low-density lipoprotein (LDL) oxidation (LDL oxidation model for antioxidant capacity, or LOMAC) was developed to assess the free radical scavenging capacity of antioxidants and the extracts of natural products. A water-soluble free radical initiator, 2,2'-azobis(amidinopropane) dihydrochloride, was used at physiological temperature (37 degrees C) to generate peroxyl radicals to catalyze lipid oxidation of LDL isolated from human plasma samples. Headspace hexanal, a major decomposition product of LDL oxidation, was measured by a headspace gas chromatograph as an indicator of antioxidant capacity of different concentrations of pure antioxidants (vitamins C and E) and the extracts of natural products (fresh apple phytochemical extracts). All vitamin C and E and apple extract concentrations tested resulted in increasing partial suppression and delay of LDL oxidation. On the basis of the median effective dose (EC(50)) calculated for each compound or extract tested, the LOMAC value of 100 g of apple against LDL oxidation was equivalent to 1470 mg of vitamin E or to 402 mg of vitamin C. This study shows that the LOMAC assay can be routinely used to analyze or screen antioxidants or phytochemical extracts against LDL oxidation to prevent cardiovascular disease. The food-specific LOMAC values will be very useful as a new alternative biomarker for future epidemiological studies of cardiovascular disease.

  1. Oxidized low-density lipoproteins induced inflammatory process during atherogenesis with aging

    NASA Astrophysics Data System (ADS)

    Larbi, Anis; Khalil, Abdelouahed; Douziech, Nadine; Guérard, Karl-Philippe; Fülöp, Tamàs

    2005-02-01

    Atherosclerosis is a chronic disease developing through decades with two life-threatening complications: myocardial infarction and stroke. Oxidized low-density lipoproteins (oxLDL) produced by oxidative modifications of LDL in the subendothelial space have been demonstrated to be critically involved in atherogenesis through their intensive pro-inflammatory activity. Recently, it was shown that oxLDL have an apoptosis-inducing effect in T cells depending on time and degree of oxidation. The goal of the current study is to elucidate the molecular mechanisms underlying the apoptotic-inducing effects of oxLDL on T lymphocytes. T cells of young and elderly subjects were incubated for various periods of time with LDL oxidized to various degrees. The proliferation, the apoptosis, the MAPK ERK1/2 activation and the expression of the Bcl-2 protein family members were measured upon different LDL treatments. Thus, more the LDL are oxidized more they induce apoptosis and this effect is highly accentuated with aging. The oxLDL decrease the activation of the surviving molecule ERK1/2 and modulate the ratio of Bax/Bcl-2 towards a pro-apoptotic profile, which is also accentuated with aging. These results partly explain why atherosclerosis is increasing with aging concomitantly to its complications.

  2. Practical technique to quantify small, dense low-density lipoprotein cholesterol using dynamic light scattering

    NASA Astrophysics Data System (ADS)

    Trirongjitmoah, Suchin; Iinaga, Kazuya; Sakurai, Toshihiro; Chiba, Hitoshi; Sriyudthsak, Mana; Shimizu, Koichi

    2016-04-01

    Quantification of small, dense low-density lipoprotein (sdLDL) cholesterol is clinically significant. We propose a practical technique to estimate the amount of sdLDL cholesterol using dynamic light scattering (DLS). An analytical solution in a closed form has newly been obtained to estimate the weight fraction of one species of scatterers in the DLS measurement of two species of scatterers. Using this solution, we can quantify the sdLDL cholesterol amount from the amounts of the low-density lipoprotein cholesterol and the high-density lipoprotein (HDL) cholesterol, which are commonly obtained through clinical tests. The accuracy of the proposed technique was confirmed experimentally using latex spheres with known size distributions. The applicability of the proposed technique was examined using samples of human blood serum. The possibility of estimating the sdLDL amount using the HDL data was demonstrated. These results suggest that the quantitative estimation of sdLDL amounts using DLS is feasible for point-of-care testing in clinical practice.

  3. [Study on the selective removal of plasma low-density lipoprotein and fibrinogen by degraded carrageenan].

    PubMed

    Cong, Haixia; Yin, Liang; Fang, Bo; Du, Longbing; Zhao, Hui; Chen, Jingling; You, Chao

    2010-08-01

    The selective removal of low density lipoprotein (LDL) and fibrinogen (Fib) by degraded carrageenan was studied by the present authors. Degraded carrageenan was prepared by acid with carrageenan as the main material. The effects of acid conditions on the molecular weight were investigated, and the proper reaction conditions were ascertained. The results of infrared spectrometry indicated that the degraded carrageenan is a heparin-like polysaccharide. Then the selective removal of LDL/Fibrinogen by degraded carrageenan was studied. When molecular weight was about 10,000, pH was 5.10 and the concentration of degraded carrageenan was 800 mg/L, the average reduction percentages were 60.0% for total cholesterol(TC), 79.4% for LDL and very low-density lipoprotein (VLDL), and 93.8% for fibrinogen. There were no significant changes with relation to the level of high-density lipoprotein (HDL) and total protein (TP). So, degraded carrageenan was shown to be of good selectivity on plasma LDL/Fibrinogen apheresis.

  4. Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor.

    PubMed

    Lambert, Gilles; Jarnoux, Anne-Laure; Pineau, Thierry; Pape, Olivier; Chetiveaux, Maud; Laboisse, Christian; Krempf, Michel; Costet, Philippe

    2006-10-01

    Several proprotein convertase subtilisin kexin type 9 (PCSK9) mutations lead to familial hypercholesterolemia by virtue of its role as a negative modulator of the low-density lipoprotein receptor (LDLr). Here, we uncover that upon dietary challenge, the down-regulation of the LDLr is also a key mechanism by which PCSK9 modulates the hepatic production of apolipoprotein-B-containing lipoproteins. Thus, adenoviral-mediated overexpression of PCSK9 in 24-h fasted mice results in massive hyperlipidemia, due to a striking increase in very-low-density lipoprotein (VLDL) triglycerides and apolipoprotein B100 hepatic output. Similar studies in LDLr (-/-) mice demonstrate that PCSK9-mediated alteration of VLDL output in the fasted state requires the LDLr. This increased production of VLDL was associated with a concomitant reduction of intrahepatic lipid stores as well as a lack of down-regulation of peroxisome proliferator-activated receptor-alpha activity and target genes expression. Finally, we show that PCSK9 hepatic expression is inhibited by the hypotriglyceridemic peroxisome proliferator-activated receptor-alpha agonist fenofibrate. In summary, the negative modulation of LDLr expression by PCSK9, which decreases plasma LDL clearance, also promotes an overproduction of nascent VLDL in vivo upon fasting.

  5. Mechanisms of metal ion-dependent oxidation of human low density lipoprotein.

    PubMed

    Lynch, S M; Frei, B

    1996-04-01

    Although either copper or iron is essential for oxidation of human low density lipoprotein (LDL) by vascular cells, the mechanism is unknown. In our experiments copper- and iron-mediated LDL oxidation was found to proceed by different mechanisms. Oxidation of LDL by iron requires superoxide and proceeds by a hydroxyl radical-independent mechanism involving reduction of iron from the ferric to the ferrous form. In contrast, copper-mediated LDL oxidation involves direct reduction of copper from the cupric to the cuprous form by LDL.

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

    SciTech Connect

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

    2006-06-14

    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.

  7. Umbilical Cord Blood Transplantation-associated Nephrotic Syndrome Successfully Treated by Low-density Lipoprotein Apheresis

    PubMed Central

    Sugawara, Yuka; Honda, Kenjiro; Katagiri, Daisuke; Nakamura, Motonobu; Kawakami, Takahisa; Nasu, Ryo; Hayashi, Akimasa; Shintani, Yukako; Tojo, Akihiro; Noiri, Eisei; Kurokawa, Mineo; Fukayama, Masashi; Nangaku, Masaomi

    2016-01-01

    The development of nephrotic syndrome (NS) after umbilical cord transplantation (UBT) has been reported in only four cases to date. We herein report the case of a 50-year-old woman who developed NS 94 days after UBT. She fell into oliguria and required dialysis. A kidney biopsy revealed focal and segmental glomerulosclerosis. Although glucocorticoid monotherapy did not improve her condition, the addition of low-density lipoprotein (LDL) apheresis resulted in remission of NS, a drastic improvement in her renal function, and withdrawal from dialysis. To the best of our knowledge, this is the first report of UBT-associated NS treated with LDL apheresis. PMID:27725544

  8. Low-density lipoprotein and apolipoprotein B: clinical use in patients with coronary heart disease.

    PubMed

    Cromwell, William C; Barringer, Thomas A

    2009-11-01

    Managing low-density lipoprotein (LDL) is an integral part of clinical practice. What remains controversial is whether we are using the best measure of LDL quantity for this purpose. Historically, the cholesterol content of LDL particles (LDLC) has been used to express LDL quantity. However, because of variability in the cholesterol carried in LDL particles, frequent disagreement occurs between LDLC and particle measures of LDL quantity, including apolipoprotein B-100 (apo B) or nuclear magnetic resonance (NMR) LDL particle number (LDL-P). Studies consistently demonstrate apo B and LDL-P are superior predictors of coronary heart disease (CHD) risk and superior indicators of low CHD risk on lipid-lowering therapy. Recent recommendations advocate that, in addition to LDLC and non-high-density lipoprotein cholesterol, apo B (or NMR LDL-P) be used as a target of therapy. This article reviews the rationale supporting these recommendations and provides a model for integrating LDL particle measures in clinical practice.

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

    SciTech Connect

    Frei, B. )

    1991-12-01

    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.

  10. The low-density lipoprotein receptor gene family: a cellular Swiss army knife?

    PubMed

    Nykjaer, Anders; Willnow, Thomas E

    2002-06-01

    The low-density lipoprotein receptor gene family is an evolutionarily conserved group of cell-surface receptors produced by mammals and other organisms. Initially thought to be endocytic receptors that mediate the uptake of lipoproteins, recent findings have shown that these receptors have other roles in a range of cellular processes. Among other activities, members of this family act as signal transducers in neuronal migration processes, regulate synaptic plasticity or control vitamin homeostasis. Such multifunctionality is achieved by interaction with diverse cell-surface proteins including glycolipid-anchored receptors, G-protein-coupled receptors and ion channels. Here, we review the molecular interactions of this protein family with other cell-surface proteins that provide specificity and versatility - a versatility that may be reminiscent of a cellular Swiss army knife.

  11. Correlation of Friedewald's calculated low-density lipoprotein cholesterol levels with direct low-density lipoprotein cholesterol levels in a tertiary care hospital.

    PubMed

    Nanda, Sunil Kumar; Bharathy, M; Dinakaran, Asha; Ray, Lopamudra; Ravichandran, K

    2017-01-01

    One of the risk factors for the development of coronary heart disease is high low-density lipoprotein (LDL) cholesterol levels. National Cholesterol Education Program ATP III guidelines suggest drug therapy to be considered at LDL-cholesterol levels >130 mg/dl. This makes accurate reporting of LDL cholesterol crucial in the management of Coronary heart disease. Estimation of LDL cholesterol by direct LDL method is accurate, but it is expensive. Hence, We compared Friedewald's calculated LDL values with direct LDL values. To evaluate the correlation of Friedewalds calculated LDL with direct LDL method. We compared LDL cholesterol measured by Friedewald's formula with direct LDL method in 248 samples between the age group of 20-70 years. Paired t-test was used to test the difference in LDL concentration obtained by a direct method and Friedewald's formula. The level of significance was taken as P < 0.05. Pearsons correlation formula was used to test the correlation between direct LDL values with Friedewald's formula. There was no significant difference between the direct LDL values when compared to calculated LDL by Friedewalds formula (P = 0.140). Pearson correlation showed there exists good correlation between direct LDL versus Friedewalds formula (correlation coefficient = 0.98). The correlation between direct LDL versus Friedewalds calculated LDL was best at triglycerides values between 101 and 200 mg/dl. This study indicates calculated LDL by Friedewalds equation can be used instead of direct LDL in patients who cannot afford direct LDL method.

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

    PubMed Central

    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

    2014-01-01

    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

  13. Apolipoprotein C-III and the Metabolic Basis for Hypertriglyceridemia and the Dense Low-Density Lipoprotein Phenotype

    PubMed Central

    Zheng, Chunyu; Khoo, Christina; Furtado, Jeremy; Sacks, Frank M.

    2011-01-01

    Background Here, we aim to identify defects of apolipoprotein (apo) B lipoprotein metabolism that characterize hypertriglyceridemia, focusing on apoC-III and apoE. Methods and Results We studied the transport of plasma apoB within 21 distinct subfractions as separated by anti–apoC-III and anti–apoE immunoaffinity chromatography and ultracentrifugation in 9 patients with moderate hypertriglyceridemia and 12 normotriglyceridemic control subjects. Hypertriglyceridemia was characterized by a 3-fold higher liver secretion of very low-density lipoprotein (VLDL) that had apoC-III but not apoE and a 50% lower secretion of VLDL with both apoC-III and apoE (both P<0.05). This shift in VLDL secretion pattern from apoE to apoC-III resulted in significantly reduced clearance of light VLDL (−39%; P<0.05), compatible with the antagonizing effects of apoC-III on apoE-induced clearance of triglyceride-rich lipoproteins. In addition, rate constants for clearance were reduced for apoE-containing triglyceride-rich lipoproteins in hypertriglyceridemia, associated with increased apoC-III contents of these particles. LDL distribution shifted from light and medium LDL to dense LDL in hypertriglyceridemia through a quartet of kinetic perturbations: increased flux from apoC-III–containing triglyceride-rich lipoproteins, a shift in liver LDL secretion pattern from light to dense LDL, an increased conversion rate from light and medium LDL to dense LDL, and retarded catabolism of dense LDL. Conclusions These results support a central role for apoC-III in metabolic defects leading to hypertriglyceridemia. Triglyceride-rich lipoprotein metabolism shifts from an apoE-dominated system in normotriglyceridemic participants characterized by rapid clearance from circulation of VLDL to an apoC-III–dominated system in hypertriglyceridemic patients characterized by reduced clearance of triglyceride-rich lipoproteins and the formation of the dense LDL phenotype. PMID:20368524

  14. Polyunsaturated fatty acid enrichment enhances endothelial cell-induced low-density-lipoprotein peroxidation.

    PubMed Central

    Mazière, C; Dantin, F; Conte, M A; Degonville, J; Ali, D; Dubois, F; Mazière, J C

    1998-01-01

    Oxidative modification of low-density lipoprotein (LDL) is an important feature in the initiation and progression of atherosclerosis. LDL modification by endothelial cells was studied after supplementation of the cells with oleic acid and polyunsaturated fatty acids (PUFA) of the n-6 and n-3 series. In terms of the lipid peroxidation product [thiobarbituric acid reactive substances (TBARS)] content and diene level of the LDL particle, oleic acid had no significant effect, and linoleic acid was poorly effective. Gamma linolenic acid (C18:3,n-6) and arachidonic acid (C20:4,n-6) increased by about 1.6-1.9-fold the cell-mediated LDL modification. PUFA from the n-3 series, alpha linolenic acid (C18:3,n-3), eicosapentaenoic acid (C20:5,n-3) and docosahexaenoic acid (C22:6,n-3), induced a less marked effect (1. 3-1.6-fold increase). The relative electrophoretic mobility of the LDL particle and its degradation by macrophages were enhanced in parallel. Concomitantly, PUFA stimulated superoxide anion secretion by endothelial cells. The intracellular TBARS content was also increased by PUFA. Comparison of PUFA from the two series indicates a good correlation between LDL oxidative modification, superoxide anion secretion and intracellular lipid peroxidation. The lipophilic antioxidant vitamin E decreased the basal as well as the PUFA-stimulated LDL peroxidation. These results indicate that PUFAs with a high degree of unsaturation of the n-6 and n-3 series could accelerate cell-mediated LDL peroxidation and thus aggravate the atherosclerotic process. PMID:9806884

  15. Oxidized low-density lipoprotein-induced apoptotic dendritic cells as a novel therapy for atherosclerosis.

    PubMed

    Frodermann, Vanessa; van Puijvelde, Gijs H M; Wierts, Laura; Lagraauw, H Maxime; Foks, Amanda C; van Santbrink, Peter J; Bot, Ilze; Kuiper, Johan; de Jager, Saskia C A

    2015-03-01

    Modulation of immune responses may form a powerful approach to treat atherosclerosis. It was shown that clearance of apoptotic cells results in tolerance induction to cleared Ags by dendritic cells (DCs); however, this seems impaired in atherosclerosis because Ag-specific tolerance is lacking. This could result, in part, from decreased emigration of DCs from atherosclerotic lesions because of the high-cholesterol environment. Nonetheless, local induction of anti-inflammatory responses by apoptotic cell clearance seems to dampen atherosclerosis, because inhibition of apoptotic cell clearance worsens atherosclerosis. In this study, we assessed whether i.v. administration of oxLDL-induced apoptotic DCs (apop(ox)-DCs) and, as a control, unpulsed apoptotic DCs could modulate atherosclerosis by inducing tolerance. Adoptive transfer of apop(ox)-DCs into low-density lipoprotein receptor knockout mice either before or during feeding of a Western-type diet resulted in increased numbers of CD103(+) tolerogenic splenic DCs, with a concomitant increase in regulatory T cells. Interestingly, both types of apoptotic DCs induced an immediate 40% decrease in Ly-6C(hi) monocyte numbers and a 50% decrease in circulating CCL2 levels, but only apop(ox)-DC treatment resulted in long-term effects on monocytes and CCL2 levels. Although initial lesion development was reduced by 40% in both treatment groups, only apop(ox)-DC treatment prevented lesion progression by 28%. Moreover, progressed lesions of apop(ox)-DC-treated mice showed a robust 45% increase in collagen content, indicating an enhanced stability of lesions. Our findings clearly show that apoptotic DC treatment significantly decreases lesion development, but only apop(ox)-DCs can positively modulate lesion progression and stability. These findings may translate into a safe treatment for patients with established cardiovascular diseases using patient-derived apop(ox)-DCs. Copyright © 2015 by The American Association of

  16. Vitamin A Decreases Cytotoxicity of Oxidized Low-Density Lipoprotein in Patients with Atherosclerosis.

    PubMed

    Mahmoudi, Mohammad Jafar; Saboor-Yaraghi, Ali-Akbar; Zabetian-Targhi, Fateme; Siassi, Fereydoon; Zarnani, Amir Hassan; Eshraghian, Mohammad Reza; Shokri, Fazel; Rezaei, Nima; Kalikias, Yas; Mahmoudi, Maryam

    2016-01-01

    Oxidized low-density lipoprotein (ox-LDL) is implicated in initiation and progression of atherosclerosis. Previously, we found that ox-LDL increases vulnerability of peripheral blood mononuclear cells (PBMCs) in atherosclerotic patients compared to controls. Vitamin A induces proliferation of PBMCs. The aim of this study was to determine the effect of vitamin A supplementation on PBMC survival against LDL and different doses of ox-LDL. In this double-blind placebo-controlled trial, we recruited 35 atherosclerotic patients and 38 healthy controls and randomly allocated them into placebo and vitamin A groups, which received either placebo or 25,000 IU/day of vitamin A for 3 months. PBMCs were isolated, cultured, and stimulated by 1 µg/mL LDL as well as 1 µg/mL and 50 µg/mL ox-LDL. The stimulation indexes (SIs) of PBMCs were calculated to identify cell viability. Additionally, the circulating ox-LDL levels were measured by ELISA. Viability of PBMCs stimulated by 50 µg/mL ox-LDL significantly increased following vitamin A supplementation in patients (p < 0.01). The levels of circulating ox-LDL were not changed by vitamin A treatment. Ox-LDL levels were strongly and positively correlated to SI of PBMCs stimulated by 1 µg/mL LDL and1 µg/mL ox-LDL in all groups. Vitamin A decreases cytotoxicity of high-dose ox-LDL and improves PBMC viability. The protective effect of vitamin A is not mediated by an antioxidative mechanism, but may instead have been due to intracellular protection of the apoptotic machinery or induction of proliferation of the cells. Higher levels of ox-LDL increase PBMC irritability in all participants.

  17. Low-Density Lipoprotein Receptor Contributes to β-Carotene Uptake in the Maternal Liver

    PubMed Central

    Shete, Varsha; Costabile, Brianna K.; Kim, Youn-Kyung; Quadro, Loredana

    2016-01-01

    Vitamin A regulates many essential mammalian biological processes, including embryonic development. β-carotene is the main source of vitamin A in the human diet. Once ingested, it is packaged into lipoproteins, predominantly low-density lipoproteins (LDL), and transported to different sites within the body, including the liver and developing tissues, where it can either be stored or metabolized to retinoids (vitamin A and its derivatives). The molecular mechanisms of β-carotene uptake by the liver or developing tissues remain elusive. Here, we investigated the role of the LDL receptor (LDLr) in β-carotene uptake by maternal liver, placenta and embryo. We administered a single dose of β-carotene to Ldlr+/− and Ldlr−/− pregnant mice via intraperitoneal injection at mid-gestation and monitored the changes in β-carotene content among maternal lipoproteins and the liver, as well as the accumulation of β-carotene in the placental–fetal unit. We showed an abnormal β-carotene distribution among serum lipoproteins and reduced hepatic β-carotene uptake in Ldlr−/− dams. These data strongly imply that LDLr significantly contributes to β-carotene uptake in the adult mouse liver. In contrast, LDLr does not seem to mediate acquisition of β-carotene by the placental–fetal unit. PMID:27916814

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

    SciTech Connect

    Terpstra, A.H.; Nicolosi, R.J.; Herbert, P.N. )

    1989-11-01

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

  19. Effect of phytosterols on copper lipid peroxidation of human low-density lipoproteins.

    PubMed

    Ferretti, Gianna; Bacchetti, Tiziana; Masciangelo, Simona; Bicchiega, Virginia

    2010-03-01

    Phytosterols and stanols have received much attention in the past several years because of their cholesterol-lowering properties, and several studies have shown a protective effect against cardiovascular disease and colon and breast cancer development. A significant decrease of plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B has been demonstrated in subjects whose diet was supplemented with 2g/d of plant sterols. Changes in plasma lipoprotein levels were associated with a decrease of oxidized LDL, suggesting that plant sterols could exert an antioxidant effect. The aim of the present study was to further investigate the interaction between the major dietary phytosterols and plasma lipoproteins. Moreover, their antioxidant effect against in vitro-induced lipid peroxidation of human LDL was investigated. Susceptibility to copper-induced lipid peroxidation was investigated in LDLs isolated from plasma of normolipemic subjects. Concentrations of beta-sitosterol, campesterol, and stigmasterol ranging from 5 to 50 microM were studied. Analyses of the emission fluorescence spectra of tryptophan and of the probe 6-dodecanoyl-2-dimethyl-aminoaphthalene were used to investigate the effect of phytosterols on apoprotein structure and physicochemical properties of LDL. Our results demonstrated that phytosterols exert an inhibitory effect against copper-induced lipid peroxidation of LDLs, as shown by the lowered levels of conjugated dienes in oxidized lipoproteins incubated with different concentrations of plant sterols (5-50 microM). Moreover, analysis of fluorescence emission spectra of tryptophan and 6-dodecanoyl-2-dimethyl-aminoaphthalene demonstrated that phytosterols prevent the alterations of apoprotein structure and physicochemical properties associated with copper-triggered lipid peroxidation of lipoproteins. We suggest that the effect exerted by beta-sitosterol, stigmasterol, and campesterol against lipid peroxidation of LDL possibly related to

  20. CD36 binds oxidized low density lipoprotein (LDL) in a mechanism dependent upon fatty acid binding.

    PubMed

    Jay, Anthony G; Chen, Alexander N; Paz, Miguel A; Hung, Justin P; Hamilton, James A

    2015-02-20

    The association of unesterified fatty acid (FA) with the scavenger receptor CD36 has been actively researched, with focuses on FA and oxidized low density lipoprotein (oxLDL) uptake. CD36 has been shown to bind FA, but this interaction has been poorly characterized to date. To gain new insights into the physiological relevance of binding of FA to CD36, we characterized FA binding to the ectodomain of CD36 by the biophysical method surface plasmon resonance. Five structurally distinct FAs (saturated, monounsaturated (cis and trans), polyunsaturated, and oxidized) were pulsed across surface plasmon resonance channels, generating association and dissociation binding curves. Except for the oxidized FA HODE, all FAs bound to CD36, with rapid association and dissociation kinetics similar to HSA. Next, to elucidate the role that each FA might play in CD36-mediated oxLDL uptake, we used a fluorescent oxLDL (Dii-oxLDL) live cell assay with confocal microscopy imaging. CD36-mediated uptake in serum-free medium was very low but greatly increased when serum was present. The addition of exogenous FA in serum-free medium increased oxLDL binding and uptake to levels found with serum and affected CD36 plasma membrane distribution. Binding/uptake of oxLDL was dependent upon the FA dose, except for docosahexaenoic acid, which exhibited binding to CD36 but did not activate the uptake of oxLDL. HODE also did not affect oxLDL uptake. High affinity FA binding to CD36 and the effects of each FA on oxLDL uptake have important implications for protein conformation, binding of other ligands, functional properties of CD36, and high plasma FA levels in obesity and type 2 diabetes.

  1. Carbamylated low-density lipoprotein induces oxidative stress and accelerated senescence in human endothelial progenitor cells.

    PubMed

    Carracedo, Julia; Merino, Ana; Briceño, Carolina; Soriano, Sagrario; Buendía, Paula; Calleros, Laura; Rodriguez, Mariano; Martín-Malo, Alejandro; Aljama, Pedro; Ramírez, Rafael

    2011-04-01

    Carbamylated low-density lipoprotein (cLDL) plays a role in atherosclerosis. In this study we evaluate the effect of uremia on LDL carbamylation and the effect of cLDL and oxidized LDL (oxLDL; 200 μg/ml) on number, function, and genomic stability of endothelial progenitor cells (EPCs) obtained from healthy volunteers. cLDL was generated after incubation of native LDL (nLDL) with uremic serum from patients with chronic kidney disease (CKD) stages 2-4. Oxidative stress was measured by flow cytometry and fluorescent microscopy, mitochondrial depolarization by flow cytometry, senescence by β-galactosidase activity and telomere length, and DNA damage by phosphorylated histone H2AX (γH2AX). The percentage of cLDL by uremic serum was related to the severity of CKD. Compared with nLDL, cLDL induced an increase in oxidative stress (62±5 vs. 8±3%, P<0.001) and cells with mitochondrial depolarization (73±7 vs. 9±5%, P<0.001), and a decrease in EPC proliferation and angiogenesis. cLDL also induced accelerated senescence (73±16 vs. 12±9%, P<0.001), which was associated with a decrease in the expression of γH2AX (62±9 vs. 5±3%, P<0.001). The degree of injury induced by cLDL was comparable to that observed with oxLDL. This study supports the hypothesis that cLDL triggers genomic damage in EPCs, resulting in premature senescence. We can, therefore, hypothesize that EPCs injury by cLDL contributes to an increase in atherosclerotic disease in CKD.

  2. Very low-density lipoprotein/lipo-viro particles reverse lipoprotein lipase-mediated inhibition of hepatitis C virus infection via apolipoprotein C-III.

    PubMed

    Sun, Hung-Yu; Lin, Chun-Chieh; Lee, Jin-Ching; Wang, Shainn-Wei; Cheng, Pin-Nan; Wu, I-Chin; Chang, Ting-Tsung; Lai, Ming-Derg; Shieh, Dar-Bin; Young, Kung-Chia

    2013-08-01

    Circulating hepatitis C virus (HCV) virions are associated with triglyceride-rich lipoproteins, including very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), designated as lipo-viro-particles (LVPs). Previous studies showed that lipoprotein lipase (LPL), a key enzyme for hydrolysing the triglyceride in VLDL to finally become LDL, may suppress HCV infection. This investigation considers the regulation of LPL by lipoproteins and LVPs, and their roles in the LPL-mediated anti-HCV function. The lipoproteins were fractionated from normolipidemic blood samples using iodixanol gradients. Subsequent immunoglobulin-affinity purification from the canonical VLDL and LDL yielded the corresponding VLDL-LVP and LDL-LVP. Apolipoprotein (apo) Cs, LPL activity and HCV infection were quantified. A higher triglyceride/cholesterol ratio of LDL was found more in HCV-infected donors than in healthy volunteers, and the triglyceride/cholesterol ratio of LDL-LVP was much increased, suggesting that the LPL hydrolysis of triglyceride may be impaired. VLDL, VLDL-LVP, LDL-LVP, but not LDL, suppressed LPL lipolytic activity, which was restored by antibodies that recognised apoC-III/-IV and correlated with the steadily abundant apoC-III/-IV quantities in those particles. In a cell-based system, treatment with VLDL and LVPs reversed the LPL-mediated inhibition of HCV infection in apoC-III/-IV-dependent manners. A multivariate logistic regression revealed that plasma HCV viral loads correlated negatively with LPL lipolytic activity, but positively with the apoC-III content of VLDL. Additionally, apoC-III in VLDL was associated with a higher proportion of HCV-RNA than was IgG. This study reveals that LPL is an anti-HCV factor, and that apoC-III in VLDL and LVPs reduces the LPL-mediated inhibition of HCV infection.

  3. Optimal Low-Density Lipoprotein Cholesterol for Cardiovascular Prevention: How Low Should We Go?

    PubMed

    Anderson, Todd J

    2017-03-01

    The treatment of dyslipidemia with lifestyle interventions and statin-based therapy has been an important defense against atherosclerotic cardiovascular disease and its complications. It has been well documented for more than 2 decades that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) reduce the risk of events. The evolution of drug development and randomized clinical trials in cardiovascular medicine has resulted in the conclusion that lower cholesterol concentrations result in greater benefit. However, how aggressive one should be in lowering cholesterol levels and to what level has not been definitively established. In this brief review I aim to defend the hypothesis that lower is better on the basis of the evidence to date. This will include indirect evidence from randomized clinical trials with statins and novel lipid-modifying drugs. In addition, there is a wealth of epidemiology and Mendelian randomization genetic data to support this. Also, on-treatment low-density lipoprotein cholesterol concentrations show a robust relationship with cardiovascular disease events. Finally, most national guidelines groups around the world continue to advocate for a treat to target philosophy. As such, the prevailing philosophy is that lowering low-density lipoprotein cholesterol to very low levels is our best preventative strategy particularly for those at the highest risk. We eagerly await the results of ongoing clinical trials that will more firmly establish if this concept will ultimately be proven correct.

  4. Targeting PCSK9 as a promising new mechanism for lowering low-density lipoprotein cholesterol.

    PubMed

    Della Badia, Laura A; Elshourbagy, Nabil A; Mousa, Shaker A

    2016-08-01

    Statins and other lipid-lowering drugs have dominated the market for many years for achievement of recommended levels of low-density lipoprotein cholesterol (LDL-C). However, a substantial number of high-risk patients are unable to achieve the LDL-C goal. Proprotein convertase subtilisin/kexin 9 (PCSK9) has recently emerged as a new, promising key therapeutic target for hypercholesterolemia. PCSK9 is a protease involved in chaperoning the low-density lipoprotein receptor to the process of degradation. PCSK9 inhibitors and statins effectively lower LDL-C. The PCSK9 inhibitors decrease the degradation of the LDL receptors, whereas statins mainly interfere with the synthetic machinery of cholesterol by inhibiting the key rate limiting enzyme, the HMG CoA reductase. PCSK9 inhibitors are currently being developed as monoclonal antibodies for their primary use in lowering LDL-C. They may be especially useful for patients with homozygous familial hypercholesterolemia, who at present receive minimal benefit from traditional statin therapy. The monoclonal antibody PCSK9 inhibitors, recently granted FDA approval, show the most promising safety and efficacy profile compared to other, newer LDL-C lowering therapies. This review will primarily focus on the safety and efficacy of monoclonal antibody PCSK9 inhibitors in comparison to statins. The review will also address new, alternative PCSK9 targeting drug classes such as small molecules, gene silencing agents, apolipoprotein B antisense oligonucleotides, and microsomal triglyceride transfer protein inhibitors.

  5. Evaluation of bacteriochlorophyll-reconstituted low-density lipoprotein nanoparticles for photodynamic therapy efficacy in vivo

    PubMed Central

    Marotta, Diane E; Cao, Weiguo; Wileyto, E Paul; Li, Hui; Corbin, Ian; Rickter, Elizabeth; Glickson, Jerry D; Chance, Britton; Zheng, Gang; Busch, Theresa M

    2011-01-01

    Aim To evaluate the novel nanoparticle reconstituted bacteriochlorin e6 bisoleate low-density lipoprotein (r-Bchl-BOA-LDL) for its efficacy as a photodynamic therapy agent delivery system in xenografts of human hepatoblastoma G2 (HepG2) tumors. Materials & methods Bchl-BOA was encapsulated in the nanoparticle low-density lipoprotein (LDL), a native particle whose receptor’s overexpression is a cancer signature for a number of neoplasms. Evaluation of r-Bchl-BOA-LDL as a potential photosensitizer was performed using a tumor response and foot response assay. Results & discussion When compared with controls, tumor regrowth was significantly delayed at injected murine doses of 2 µmole/kg r-Bchl-BOA-LDL after illumination at fluences of 125, 150 or 175 J/cm2. Foot response assays showed that although normal tissue toxicity accompanied the higher fluences it was significantly reduced at the lowest fluence tested. Conclusion This research demonstrates that r-Bchl-BOA-LDL is an effective photosensitizer and a promising candidate for further investigation. PMID:21542686

  6. Protective effects of endomorphins, endogenous opioid peptides in the brain, on human low density lipoprotein oxidation.

    PubMed

    Lin, Xin; Xue, Li-Ying; Wang, Rui; Zhao, Qian-Yu; Chen, Qiang

    2006-03-01

    Neurodegenerative disorders are associated with oxidative stress. Low density lipoprotein (LDL) exists in the brain and is especially sensitive to oxidative damage. Oxidative modification of LDL has been implicated in the pathogenesis of neurodegenerative diseases. Therefore, protecting LDL from oxidation may be essential in the brain. The antioxidative effects of endomorphin 1 (EM1) and endomorphin 2 (EM2), endogenous opioid peptides in the brain, on LDL oxidation has been investigated in vitro. The peroxidation was initiated by either copper ions or a water-soluble initiator 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH). Oxidation of the LDL lipid moiety was monitored by measuring conjugated dienes, thiobarbituric acid reactive substances, and the relative electrophoretic mobility. Low density lipoprotein oxidative modifications were assessed by evaluating apoB carbonylation and fragmentation. Endomorphins markedly and in a concentration-dependent manner inhibited Cu2+ and AAPH induced the oxidation of LDL, due to the free radical scavenging effects of endomorphins. In all assay systems, EM1 was more potent than EM2 and l-glutathione, a major intracellular water-soluble antioxidant. We propose that endomorphins provide protection against free radical-induced neurodegenerative disorders.

  7. Systematic review: association of low-density lipoprotein subfractions with cardiovascular outcomes.

    PubMed

    Ip, Stanley; Lichtenstein, Alice H; Chung, Mei; Lau, Joseph; Balk, Ethan M

    2009-04-07

    Measures of low-density lipoprotein (LDL) subfractions have been proposed as an independent risk factor for cardiovascular disease. To review published studies that reported relationships between LDL subfractions and cardiovascular outcomes. MEDLINE (1950 to 5 January 2009), CAB Abstracts (1973 to 30 June 2008), and Cochrane Central Register of Controlled Trials (2nd quarter of 2008), limited to English-language studies. 3 reviewers selected longitudinal studies with 10 or more participants that reported an association between LDL subfractions and incidence or severity of cardiovascular disease and in which plasma samples were collected before outcome determination. Data were extracted from 24 studies. The 10 studies that used analytical methods available for clinical use (all of which used nuclear magnetic resonance) had full data extraction, including quality assessment (good, fair, or poor). All studies were extracted by 1 researcher and verified by another. All 24 studies, and the subset of 10 nuclear magnetic resonance studies, were heterogeneous in terms of the specific tests analyzed, analytical methods used, participants investigated, and outcomes measured. Higher LDL particle number was consistently associated with increased risk for cardiovascular disease, independent of other lipid measurements. Other LDL subfractions were generally not associated with cardiovascular disease after adjustment for cholesterol concentrations. No study evaluated the incremental value of LDL subfractions beyond traditional cardiovascular risk factors or their test performance. Publication bias was a possibility. Higher LDL particle number has been associated with cardiovascular disease incidence, but studies have not determined whether any measures of LDL subfractions add incremental benefit to traditional risk factor assessment. Routine use of clinically available LDL subfraction tests to estimate cardiovascular disease risk is premature.

  8. Utilization of ascites plasma very low density lipoprotein triglycerides by Ehrlich cells.

    PubMed

    Brenneman, D E; Spector, A A

    1974-07-01

    Much of the lipid present in the ascites plasma in which Ehrlich cells grow is contained in very low density lipoproteins (VLDL). Chemical measurements indicated that triglycerides were taken up by the cells during in vitro incubation with ascites VLDL. When tracer amounts of radioactive triolein were incorporated into the ascites VLDL, the percentage uptakes of glyceryl tri[1-(14)C]oleate and triglycerides measured chemically were similar. The cells also took up [2-(3)H]glyceryl trioleate that was added to VLDL, but the percentage of available (3)H recovered in the cell lipids was 30-40% less than that of (1 4)C from glyceryl tri[1-(1 4)C]oleate. This difference was accounted for by water-soluble (3)H that accumulated in the incubation medium, suggesting that extensive hydrolysis accompanied the uptake of VLDL triglycerides. Radioactive fatty acids derived from the VLDL triglycerides were incorporated into cell phospholipids, glycerides, and free fatty acids, and they also were oxidized to CO(2). Triglyceride utilization increased as the VLDL concentration was raised. These results suggest that one function of the ascites plasma VLDL may be to supply fatty acid to the Ehrlich cells and that the availability of fatty acid to this tumor is determined in part by the ascites plasma VLDL concentration. Although Ehrlich cells incorporate almost no free glycerol into triglycerides, considerable amounts of [2-(3)H]glyceryl trioleate radioactivity were recovered in cell triglycerides. This indicates that at least some VLDL triglycerides were taken up intact. The net uptake of VLDL protein and cholesterol was very small relative to the triglyceride uptake, suggesting that intact triglycerides are transferred from the ascites VLDL to the Ehrlich cells and that hydrolysis occurs after the triglyceride is associated with the cells.

  9. Serum low-density lipoprotein levels, statin use, and cognition in patients with coronary artery disease

    PubMed Central

    Rej, Soham; Saleem, Mahwesh; Herrmann, Nathan; Stefatos, Anthi; Rau, Allison; Lanctôt, Krista L

    2016-01-01

    Aim Statins have been associated with decreased cognition due to the effects of low concentrations of low-density lipoprotein (LDL) on brain function. This has remained controversial and is particularly relevant to patients with coronary artery disease (CAD), who have an increased risk of cognitive decline and are frequently prescribed statins. This study hypothesized that low concentration of LDL is associated with poor cognition in CAD patients using statins. It also explored the association between high-dose versus low-dose statins on cognition in this population. Patients and methods Baseline cross-sectional data from a longitudinal study of 120 statin-using CAD patients were examined (mean statin duration 25±43 months). The main outcomes were measures of global cognition and cognitive domains, with poor cognition defined as cognitive performance ≤1 standard deviation below the population age and education adjusted means. A battery of cognitive tests was used to assess verbal memory, executive function, speed of processing, visuospatial memory, and global cognition. Adjusting for age, sex, education, and other covariates, multivariable logistic regression analyses assessed associations between low LDL levels (<1.5 mmol/L), statin use, and poor cognition. Results LDL levels were not associated with global cognition or individual cognitive domains. High-dose statin use was associated with higher visuospatial memory (odds ratio, OR [95% confidence interval, CI] =0.12 [0.02–0.66], P=0.01) and executive functioning (OR =0.25 [0.06–0.99], P=0.05). This effect was independent of covariates such as LDL levels. Conclusion Low LDL levels do not appear to be associated with poor cognition in CAD patients using statins. Whether high-dose statin use may have positive effects on cognition in CAD patients could be investigated in future studies. PMID:27877045

  10. Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis.

    PubMed

    Qian, Yue-Wei; Schmidt, Robert J; Zhang, Youyan; Chu, Shaoyou; Lin, Aimin; Wang, He; Wang, Xiliang; Beyer, Thomas P; Bensch, William R; Li, Weiming; Ehsani, Mariam E; Lu, Deshun; Konrad, Robert J; Eacho, Patrick I; Moller, David E; Karathanasis, Sotirios K; Cao, Guoqing

    2007-07-01

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that regulates low density lipoprotein receptor (LDLR) protein levels. The mechanisms of this action, however, remain to be defined. We show here that recombinant human PCSK9 expressed in HEK293 cells was readily secreted into the medium, with the prosegment associated with the C-terminal domain. Secreted PCSK9 mediated cell surface LDLR degradation in a concentration- and time-dependent manner when added to HEK293 cells. Accordingly, cellular LDL uptake was significantly reduced as well. When infused directly into C57B6 mice, purified human PCSK9 substantially reduced hepatic LDLR protein levels and resulted in increased plasma LDL cholesterol. When added to culture medium, fluorescently labeled PCSK9 was endocytosed and displayed endosomal-lysosomal intracellular localization in HepG2 cells, as was demonstrated by colocalization with DiI-LDL. PCSK9 endocytosis was mediated by LDLR as LDLR deficiency (hepatocytes from LDLR null mice), or RNA interference-mediated knockdown of LDLR markedly reduced PCSK9 endocytosis. In addition, RNA interference knockdown of the autosomal recessive hypercholesterolemia (ARH) gene product also significantly reduced PCSK9 endocytosis. Biochemical analysis revealed that the LDLR extracellular domain interacted directly with secreted PCSK9; thus, overexpression of the LDLR extracellular domain was able to attenuate the reduction of cell surface LDLR levels by secreted PCSK9. Together, these results reveal that secreted PCSK9 retains biological activity, is able to bind directly to the LDLR extracellular domain, and undergoes LDLR-ARH-mediated endocytosis, leading to accelerated intracellular degradation of the LDLR.

  11. 17beta-Estradiol reverses shear-stress-mediated low density lipoprotein modifications.

    PubMed

    Hwang, Juliana; Rouhanizadeh, Mahsa; Hamilton, Ryan T; Lin, Tiantian C; Eiserich, Jason P; Hodis, Howard N; Hsiai, Tzung K

    2006-08-15

    Within arterial bifurcations or branching points, oscillatory shear stress (OSS) induces oxidative stress mainly via the reduced nicotinamide adenine dinucleodtide phosphate (NADPH) oxidase system. It is unknown whether 17beta-estradiol (E(2)) can regulate OSS-mediated low-density lipoprotein (LDL) modifications. Bovine aortic endothelial cells were pretreated with E(2) at 5 nmol/L, followed by exposure to OSS (0 +/- 3.0 dynes/cm(2) s and 60 cycles/min) in a flow system. E(2) decreased OSS-mediated NADPH oxidase mRNA expression, and E(2)-mediated (.-)NO production was mitigated by the NO synthase inhibitor N(G)-nitro-l-argenine methyl ester. The rates of O(2)(-.) production in response to OSS increased steadily as determined by superoxide-dismutase-inhibited ferricytochrome c reduction; whereas, pretreatment with E(2) decreased OSS-mediated O(2)(-.) production (n = 4, p < 0.05). In the presence of native LDL (50 microg/mL), E(2) also significantly reversed OSS-mediated LDL oxidation as determined by high-performance liquid chromatography. In the presence of O(2)(-.) donor, xanthine oxidase (XO), E(2) further reversed XO-induced LDL lipid peroxidation (n = 3, p < 0.001). Mass spectra acquired in the m/z 400-1800 range, revealed XO-mediated LDL protein nitration involving tyrosine 2535 in the alpha-2 domains, whereas pretreatment with E(2) reversed nitration, as supported by the changes in nitrotyrosine intensities. Thus, E(2) plays an indirect antioxidative role. In addition to upregulation of endothelial (.-)NO synthase and downregulation of Nox4 expression, E(2) influences LDL modifications via lipid peroxidation and protein nitration.

  12. Protective effect of oleuropein, an olive oil biophenol, on low density lipoprotein oxidizability in rabbits.

    PubMed

    Coni, E; Di Benedetto, R; Di Pasquale, M; Masella, R; Modesti, D; Mattei, R; Carlini, E A

    2000-01-01

    On the basis of the results obtained with pilot studies conducted in vitro on human low density lipoprotein (LDL) and on cell cultures (Caco-2), which had indicated the ability of certain molecules present in olive oil to inhibit prooxidative processes, an in vivo study was made of laboratory rabbits fed special diets. Three different diets were prepared: a standard diet for rabbits (diet A), a standard diet for rabbits modified by the addition of 10% (w/w) extra virgin olive oil (diet B), a modified standard diet for rabbits (diet C) differing from diet B only in the addition of 7 mg kg(-1) of oleuropein. A series of biochemical parameters was therefore identified, both in the rabbit plasma and the related isolated LDL, before and after Cu-induced oxidation. The following, in particular, were selected: (i) biophenols, vitamins E and C, uric acid, and total, free, and ester cholesterol in the plasma; (ii) proteins, triglycerides, phospholipids, and total, free, and ester cholesterol in the native LDL (for the latter, the dimensions were also measured); (iii) lipid hydroperoxides, aldehydes, conjugated dienes, and relative electrophoretic mobility (REM) in the oxidized LDL (ox-LDL). In an attempt to summarize the results obtained, it can be said that this investigation has not only verified the antioxidant efficacy of extra virgin olive oil biophenols and, in particular, of oleuropein, but has also revealed a series of thus far unknown effects of the latter on the plasmatic lipid situation. In fact, the addition of oleuropein in diet C increased the ability of LDL to resist oxidation (less conjugated diene formation) and, at the same time, reduced the plasmatic levels of total, free, and ester cholesterol (-15, -12, and -17%, respectively), giving rise to a redistribution of the lipidic components of LDL (greater phospholipid and cholesterol amounts) with an indirect effect on their dimensions (bigger by about 12%).

  13. Oxidized low-density lipoprotein is associated with advanced-stage prostate cancer.

    PubMed

    Wan, Fangning; Qin, Xiaojian; Zhang, Guiming; Lu, Xiaolin; Zhu, Yao; Zhang, Hailiang; Dai, Bo; Shi, Guohai; Ye, Dingwei

    2015-05-01

    Clinical and epidemiological data suggest coronary artery disease shares etiology with prostate cancer (PCa). The aim of this work was to assess the effects of several serum markers reported in cardiovascular disease on PCa. Serum markers (oxidized low-density lipoprotein [ox-LDL], apolipoprotein [apo] B100, and apoB48) in peripheral blood samples from 50 patients from Fudan University Shanghai Cancer Center (FUSCC) with localized or lymph node metastatic PCa were investigated in this study. Twenty-five samples from normal individuals were set as controls. We first conducted enzyme-linked immunosorbent assay analysis to select candidate markers that were significantly different between these patients and controls. Then, the clinical relevance between OLR1 (the ox-LDL receptor) expression and PCa was analyzed in The Cancer Genome Atlas (TCGA) cohort. We also investigated the function of ox-LDL in PCa cell lines in vitro. Phosphorylation protein chips were used to analyze cell signaling pathways in ox-LDL-treated PC-3 cells. The ox-LDL level was found to be significantly correlated with N stage of prostate cancer. OLR1 expression was correlated with lymph node metastasis in the TCGA cohort. In vitro, ox-LDL stimulated the proliferation, migration, and invasion of LNCaP and PC-3 in a dose-dependent manner. The results of phosphoprotein microarray illustrated that ox-LDL could influence multiple signaling pathways of PC-3. Activation of proliferation promoting signaling pathways (including β-catenin, cMyc, NF-κB, STAT1, STAT3) as well as apoptosis-associating signaling pathways (including p27, caspase-3) demonstrated that ox-LDL had complicated effects on prostate cancer. Increased serum ox-LDL level and OLR1 expression may indicate advanced-stage PCa and lymph node metastasis. Moreover, ox-LDL could stimulate PCa proliferation, migration, and invasion in vitro.

  14. Low density lipoprotein receptor-related protein 5 gene polymorphisms and osteoporosis in Thai menopausal women.

    PubMed

    Kitjaroentham, Anong; Hananantachai, Hathairad; Phonrat, Benjaluck; Preutthipan, Sangchai; Tungtrongchitr, Rungsunn

    2016-09-01

    Osteoporosis, characterized by low bone mineral density (BMD) and high bone fracture risk, is prevalent in Thai menopausal women. Genetic factors are known to play a key role in BMD. Low density lipoprotein receptor-related protein 5 (LRP5), a co-receptor in the Wnt/beta-catenin pathway, is involved in many aspects of bone biology. As coding single nucleotide polymorphisms (cSNPs) of LRP5, including A1330V (rs3736228), and Asian-related Q89R (rs41494349) and N740N (rs2306862), are associated with lowered BMD, this study aimed to determine the relationship between these LRP5 polymorphisms and BMD in 277 Thai menopausal women. Only rs3736228 deviated from the Hardy-Weinberg equilibrium of allele frequency (p = 0.022). The median, range and p value for the BMD related to each SNP parameter were compared (Mann-Whitney U test). Significant differences were observed between wild-type and risk alleles for both rs3736228 (total radial, p = 0.011; and radial 33, p = 0.001) and rs2306862 (radial 33: p = 0.015) SNPs, with no significant difference for rs41494349 SNP. Linkage disequilibrium was strong for both rs3736228 and rs2306862 SNPs. Haplotype analysis identified high CC frequency in both normal and osteopenia/osteoporosis groups, with a significant odds ratio for carrying the TT haplotype; however, this was non-significant after adjusting for age. Multivariate binary logistic regression analysis performed for rs3736228 showed that individuals with a body mass index <25 kg/m(2) had an increased risk of osteoporosis for each decade, but the polymorphism had no effect. This study did not identify LRP5 polymorphisms as a risk factor for osteoporosis in Thai menopausal women. Further studies with larger sample sizes are needed to further clarify the role of LRP5 as a genetic determinant of osteoporosis.

  15. Postprandial Clearance of Oxidized Low-Density Lipoprotein in Patients with Stroke Due to Atherosclerosis.

    PubMed

    Al Kasab, Sami; Cassarly, Christy; Le, Ngoc-Anh; Martin, Renee; Brinley, Julia; Chimowitz, Marc I; Turan, Tanya N

    2017-03-01

    Oxidized low-density lipoprotein (OxLDL) is a contributor to atherosclerosis development. OxLDL formation increases in the postprandial state due to oxidative stress in subjects with coronary artery disease (CAD) and diabetes, but has not been studied in patients with atherosclerotic stroke. We aimed to determine differences in postprandial OxLDL in patients with atherosclerotic stroke compared to stroke from other causes. Patients with ischemic stroke but no history of CAD (n = 42) were enrolled and categorized by stroke subtype as extracranial atherosclerosis (EC), n = 12; intracranial atherosclerosis (IC), n = 16; or other cause, n = 14. After fasting overnight, subjects consumed a standardized fat meal. OxLDL levels were measured at t = 0 and t = 4 hours postprandial using enzyme-linked immunosorbent assay. Comparisons between the mean changes in OxLDL between the groups were performed using the analysis of variance procedure. The IC group had the highest mean baseline level of OxLDL and the greatest decline during the postprandial period. There was a trend toward a difference in the mean change in OxLDL between the 3 groups (P = .0553). Subjects with atherosclerotic stroke (EC and IC groups) had higher fasting OxLDL and had a significant decline in OxLDL compared to those with stroke from other causes (P = .0164). Subjects with stroke due to atherosclerosis, particularly intracranially, demonstrated high fasting OxLDL and a decline in OxLDL during the postprandial period. This decline in OxLDL may indicate an accelerated clearance of OxLDL resulting from meal-induced oxidative stress. Published by Elsevier Inc.

  16. Low density lipoprotein receptor related protein 1 and 6 gene variants and ischaemic stroke risk.

    PubMed

    Harriott, A M; Heckman, M G; Rayaprolu, S; Soto-Ortolaza, A I; Diehl, N N; Kanekiyo, T; Liu, C-C; Bu, G; Malik, R; Cole, J W; Meschia, J F; Ross, O A

    2015-08-01

    Low density lipoprotein receptor related proteins (LRPs) 1 and 6 have been implicated in cerebral ischaemia. In addition, genetic variation in LRP1 and LRP6 has been linked with various factors that are related to risk of ischaemic stroke. The aim of this study was to examine the association of LRP1 and LRP6 gene variants with risk of ischaemic stroke as part of the Ischemic Stroke Genetics Study (ISGS). A Caucasian series (434 stroke patients, 319 controls) and an African American series (161 stroke patients, 116 controls) were included. Fourteen LRP6 variants and three LRP1 variants were genotyped and assessed for association with ischaemic stroke. In the Caucasian series, significant associations with ischaemic stroke were observed for LRP6 rs2075241 [odds ratio (OR) 0.42, P = 0.023], rs2302685 (OR 0.44, P = 0.049), rs7975614 (OR 0.07, P = 0.017), rs10492120 (OR 0.62, P = 0.036) and rs10743980 (OR 0.66, P = 0.037). Risk of ischaemic stroke was significantly lower for carriers of any of these five protective LRP6 variants (24.0% of subjects) compared to non-carriers (OR 0.57, P = 0.003). The protective association for LRP6 rs2075241 was observed at a similar magnitude across ischaemic stroke subtypes, whilst the effects of rs23022685, rs10492120 and rs10743980 were most apparent for cardioembolic and large vessel stroke. In the African American series, LRP1 rs11172113 was associated with an increased risk of stroke (OR 1.89, P = 0.006). The results of our preliminary study provide evidence that LRP6 and LRP1 variants may be associated with risk of ischaemic stroke. Validation in larger studies is warranted. © 2015 EAN.

  17. Influence of baseline low-density lipoprotein cholesterol values on statin therapy persistence.

    PubMed

    Citarella, Anna; Linder, Marie; Kieler, Helle; Berglind, Ingegärd Anveden; Sundström, Anders; Wettermark, Björn; Andersen, Morten

    2016-03-01

    Persistence to statins is low, in part due to lack of perception of cardiovascular (CV) risk. High values of low-density lipoprotein cholesterol (LDL-C) might increase the motivation for patients to be persistent. We investigated whether the baseline LDL-C value influences the discontinuation of statin treatment in patients with and without previous CV events. A cohort study was performed using information from the Swedish national registers concerning dispensed drugs, hospital contacts, cause of death, and socioeconomic status, and linked with data from clinical laboratories. Incident statin users 20 years of age or older and starting treatment between 2006 and 2007 were identified and followed for 1 year. Baseline LDL-C level was defined as the last available laboratory test result during 6 months before the index statin dispensing. Cox regression was used to study discontinuation and estimate the effect on persistence of the baseline LDL-C value adjusting for sex, age, income, comorbidity, previous CV events, type of prescriber, and country of birth. Subgroup analyses stratifying by previous CV events and by diagnosis of diabetes among subjects without previous CV events were performed. A total of 29,389 patients were identified; 35.4% had a previous CV event. A high baseline LDL-C value was associated with a lower discontinuation rate (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.72-0.91) in patients without previous CV events. When stratifying further by diabetes diagnosis, the association was confirmed only in patients without diabetes. No association between LDL-C and persistence was found in patients with previous CV events. High levels of LDL-C were positively associated with statin persistence in newly treated diabetes patients without previous CV events.

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

    PubMed Central

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

    2008-01-01

    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

  19. Low density lipoprotein receptor-related protein 1 dependent endosomal trapping and recycling of apolipoprotein E.

    PubMed

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

    2012-01-01

    Lipoprotein receptors from the low density lipoprotein (LDL) receptor family are multifunctional membrane proteins which can efficiently mediate endocytosis and thereby facilitate lipoprotein clearance from the plasma. The biggest member of this family, the LDL receptor-related protein 1 (LRP1), facilitates the hepatic uptake of triglyceride-rich lipoproteins (TRL) via interaction with apolipoprotein E (apoE). In contrast to the classical LDL degradation pathway, TRL disintegrate in peripheral endosomes, and core lipids and apoB are targeted along the endocytic pathway for lysosomal degradation. Notably, TRL-derived apoE remains within recycling endosomes and is then mobilized by high density lipoproteins (HDL) for re-secretion. The aim of this study is to investigate the involvement of LRP1 in the regulation of apoE recycling. Immunofluorescence studies indicate the LRP1-dependent trapping of apoE in EEA1-positive endosomes in human hepatoma cells. This processing is distinct from other LRP1 ligands such as RAP which is efficiently targeted to lysosomal compartments. Upon stimulation of HDL-induced recycling, apoE is released from LRP1-positive endosomes but is targeted to another, distinct population of early endosomes that contain HDL, but not LRP1. For subsequent analysis of the recycling capacity, we expressed the full-length human LRP1 and used an RNA interference approach to manipulate the expression levels of LRP1. In support of LRP1 determining the intracellular fate of apoE, overexpression of LRP1 significantly stimulated HDL-induced apoE recycling. Vice versa LRP1 knockdown in HEK293 cells and primary hepatocytes strongly reduced the efficiency of HDL to stimulate apoE secretion. We conclude that LRP1 enables apoE to accumulate in an early endosomal recycling compartment that serves as a pool for the intracellular formation and subsequent re-secretion of apoE-enriched HDL particles.

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

    PubMed Central

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

    2012-01-01

    Background Lipoprotein receptors from the low density lipoprotein (LDL) receptor family are multifunctional membrane proteins which can efficiently mediate endocytosis and thereby facilitate lipoprotein clearance from the plasma. The biggest member of this family, the LDL receptor-related protein 1 (LRP1), facilitates the hepatic uptake of triglyceride-rich lipoproteins (TRL) via interaction with apolipoprotein E (apoE). In contrast to the classical LDL degradation pathway, TRL disintegrate in peripheral endosomes, and core lipids and apoB are targeted along the endocytic pathway for lysosomal degradation. Notably, TRL-derived apoE remains within recycling endosomes and is then mobilized by high density lipoproteins (HDL) for re-secretion. The aim of this study is to investigate the involvement of LRP1 in the regulation of apoE recycling. Principal Findings Immunofluorescence studies indicate the LRP1-dependent trapping of apoE in EEA1-positive endosomes in human hepatoma cells. This processing is distinct from other LRP1 ligands such as RAP which is efficiently targeted to lysosomal compartments. Upon stimulation of HDL-induced recycling, apoE is released from LRP1-positive endosomes but is targeted to another, distinct population of early endosomes that contain HDL, but not LRP1. For subsequent analysis of the recycling capacity, we expressed the full-length human LRP1 and used an RNA interference approach to manipulate the expression levels of LRP1. In support of LRP1 determining the intracellular fate of apoE, overexpression of LRP1 significantly stimulated HDL-induced apoE recycling. Vice versa LRP1 knockdown in HEK293 cells and primary hepatocytes strongly reduced the efficiency of HDL to stimulate apoE secretion. Conclusion We conclude that LRP1 enables apoE to accumulate in an early endosomal recycling compartment that serves as a pool for the intracellular formation and subsequent re-secretion of apoE-enriched HDL particles. PMID:22238606

  1. Low density lipoprotein apheresis in pediatric patients with homozygous familial hypercholesterolemia.

    PubMed

    Coker, Mahmut; Ucar, Sema Kalkan; Simsek, Damla Goksen; Darcan, Sukran; Bak, Mustafa; Can, Sule

    2009-04-01

    The aim of the present study is to clarify the low density lipoprotein apheresis procedure for pediatric patients with homozygous familial hypercholesterolemia (FH) in terms of efficacy, adverse effects and difficulties. The follow-up was carried out using an open, prospective uncontrolled clinical design. Data were collected from 10 patients (with an average age of 8.4 +/- 4.7 years) with FH treated with double filtration plasmapheresis. The total time span of follow-up covered five years (30.2 +/- 17.8 months [range 9-60 months]) and more than 600 sessions (62.1 +/- 35.5 sessions per patient [range 18-120 sessions]) were evaluated. The mean low density lipoprotein cholesterol (LDL-C) pre-treatment value was 375.5 +/- 127.5 mg/dL, and the post-treatment value was 147.5 +/- 73.9 mg/dL. This corresponded to a 62.8 +/- 10.3% (43-73%) acute reduction of LDL-C, while the mean high density lipoprotein cholesterol losses amounted to 41%. The chronic reduction in LDL-C ranged from 18 to 52%, with a mean level of 36.4 +/- 11.7%. The most frequently occurring technical problems were related to blood lines: puncture difficulties (4.5%), insufficient blood flow (3.5%), and obturation of the blood lines (2.4%). The main clinical adverse effects were hypotension (0.2%), chills/feeling cold (0.1%), and nausea and vomiting (0.2%). We observed that the low pediatric patient tolerance is the main problem in compliance with treatment. In conclusion, LDL apheresis, started under the age of eight years, combined with lipid-lowering drugs, provides a safe and effective lowering of the mean LDL-C levels in pediatric homozygous FH; and there are more problems with compliance for pediatric LDL apheresis than in the adult population.

  2. A linoleate-enriched cheese product reduces low-density lipoprotein in moderately hypercholesterolemic adults.

    PubMed

    Davis, P A; Platon, J F; Gershwin, M E; Halpern, G M; Keen, C L; DiPaolo, D; Alexander, J; Ziboh, V A

    1993-10-01

    To test the effect of substituting a modified-fat cheese product into the diets of hypercholesterolemic adults. A 4-month, randomized, double-blind, crossover substitution trial. General community outpatient study. Twenty-six healthy adult volunteers (17 men, 9 women) with moderate hypercholesterolemia (total cholesterol > 5.69 mmol/L but < 7.24 mmol/L). Daily substitution of 100 g of cheese, either partial skim-milk mozzarella or modified-fat (vegetable oil) mozzarella cheese product, into participants' normal diets. Participants consumed an assigned cheese for 2 months, at which time they crossed over to consume the other study cheese. Plasma lipid and apolipoprotein levels were measured at baseline and at 2 and 4 months after initiation of the study. Compliance was assessed by body weight and by biweekly dietary records and interviews. No differences in weight or in the amount or type of calories consumed were found during the study. No statistically significant changes in lipid values resulted from consumption of mozzarella cheese. Modified-fat cheese substitution resulted in a decreased low-density lipoprotein cholesterol level when compared with levels at both baseline (-0.28 mmol/L; 95% Cl, -0.14 to -0.42 mmol/L) and during consumption of the skim-milk mozzarella cheese (-0.38 mmol/L; 95% Cl, -0.2 to -0.70 mmol/L). Findings for total cholesterol were similar. High-density lipoprotein cholesterol, plasma triglyceride, and apolipoprotein A-l and B-100 levels were unaltered. Both sexes responded similarly. A linoleate-enriched cheese product, in the absence of any other changes in diet or habits, substituted into the normal diets of hypercholesterolemic adults reduced low-density lipoprotein and plasma cholesterol levels.

  3. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.

    PubMed Central

    Aalto-Setälä, K; Fisher, E A; Chen, X; Chajek-Shaul, T; Hayek, T; Zechner, R; Walsh, A; Ramakrishnan, R; Ginsberg, H N; Breslow, J L

    1992-01-01

    not well recognized by lipoprotein receptors. Additional in vivo studies with Triton-treated mice showed increased VLDL triglyceride, but not apo B, production in the HuCIIITg mice compared with controls. Tissue culture studies with primary hepatocytes showed a modest increase in triglyceride, but not apo B or total protein, secretion in high expressor mice compared with controls. In summary, hypertriglyceridemia in HuCIIITg mice appears to result primarily from decreased tissue uptake of triglyceride-rich particles from the circulation, which is most likely due to increased apo CIII and decreased apo E on VLDL particles. the HuCIIITg mouse appears to be a suitable animal model of primary familial hypertriglyceridemia, and these studies suggest a possible mechanism for this common lipoprotein disorder. Images PMID:1430212

  4. Anti-oxidized low-density lipoprotein antibodies in myeloperoxidase–positive vasculitis patients preferentially recognize hypochlorite-modified low density lipoproteins

    PubMed Central

    Slot, M C; Theunissen, R; van Paassen, P; Damoiseaux, J G M C; Cohen Tervaert, J W

    2007-01-01

    Many patients surviving vasculitis are prone to accelerated atherosclerosis and often have enhanced levels of antibodies to oxidized low-density lipoprotein (oxLDL). To measure anti-oxLDL antibodies, oxidation of LDL is achieved with copper (Cu) or malondialdehyde (MDA). Because, in vivo, LDL may be oxidized with myeloperoxidase (MPO) or its product hypochlorite, we measured anti-hypochlorite LDL antibodies in patients with vasculitis, haemodialysis patients and healthy controls. A newly developed enzyme-linked immunosorbent assay (ELISA) was used to detect antibodies to oxLDL as modified by hypochlorite. Results are compared with data obtained by standard LDL oxidation using MDA–LDL or Cu–LDL as substrate. Results were compared between anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients (n = 93), haemodialysis (HD) patients (n = 59) and healthy controls (HC; n = 43). Furthermore, patients with MPO–ANCA-associated vasculitis (n = 47) were compared with patients with proteinase 3 (PR3)–ANCA associated vasculitis (n = 46). Optimal cut-off points were determined by receiver operator characteristic (ROC) curve analysis. Anti-oxLDL antibodies are enhanced in AAV patients (MDA–LDL and hypochlorite–LDL) and in HD patients (hypochlorite–LDL), when compared to HC. Furthermore, patients with MPO–ANCA-associated vasculitis had higher levels of antibodies to hypochlorite–LDL than patients with PR3–ANCA-associated vasculitis. Our newly developed assay, in which hypochlorite–LDL is used as substrate, seems a more sensitive assay than traditional assays to measure oxLDL antibodies. Furthermore, our results suggest that enhanced MPO-mediated LDL oxidation occurs in patients with MPO–ANCA. PMID:17521320

  5. Correlation of Friedewald's calculated low-density lipoprotein cholesterol levels with direct low-density lipoprotein cholesterol levels in a tertiary care hospital

    PubMed Central

    Nanda, Sunil Kumar; Bharathy, M; Dinakaran, Asha; Ray, Lopamudra; Ravichandran, K

    2017-01-01

    Background: One of the risk factors for the development of coronary heart disease is high low-density lipoprotein (LDL) cholesterol levels. National Cholesterol Education Program ATP III guidelines suggest drug therapy to be considered at LDL-cholesterol levels >130 mg/dl. This makes accurate reporting of LDL cholesterol crucial in the management of Coronary heart disease. Estimation of LDL cholesterol by direct LDL method is accurate, but it is expensive. Hence, We compared Friedewald's calculated LDL values with direct LDL values. Aim: To evaluate the correlation of Friedewalds calculated LDL with direct LDL method. Materials and Methods: We compared LDL cholesterol measured by Friedewald's formula with direct LDL method in 248 samples between the age group of 20–70 years. Paired t-test was used to test the difference in LDL concentration obtained by a direct method and Friedewald's formula. The level of significance was taken as P < 0.05. Pearsons correlation formula was used to test the correlation between direct LDL values with Friedewald's formula. Results: There was no significant difference between the direct LDL values when compared to calculated LDL by Friedewalds formula (P = 0.140). Pearson correlation showed there exists good correlation between direct LDL versus Friedewalds formula (correlation coefficient = 0.98). The correlation between direct LDL versus Friedewalds calculated LDL was best at triglycerides values between 101 and 200 mg/dl. Conclusion: This study indicates calculated LDL by Friedewalds equation can be used instead of direct LDL in patients who cannot afford direct LDL method. PMID:28251110

  6. ANALYSIS OF DRUG INTERACTIONS WITH VERY LOW DENSITY LIPOPROTEIN BY HIGH PERFORMANCE AFFINITY CHROMATOGRAPHY

    PubMed Central

    Sobansky, Matthew R.; Hage, David S.

    2014-01-01

    High-performance affinity chromatography (HPAC) was utilized to examine the binding of very low density lipoprotein (VLDL) with drugs, using R/S-propranolol as a model. These studies indicated that two mechanisms existed for the binding of R- and S-propranolol with VLDL. The first mechanism involved non-saturable partitioning of these drugs with VLDL, which probably occurred with the lipoprotein's non-polar core. This partitioning was described by overall affinity constants of 1.2 (± 0.3) × 106 M-1 for R-propranolol and 2.4 (± 0.6) × 106 M-1 for S-propranolol at pH 7.4 and 37 °C. The second mechanism occurred through saturable binding by these drugs at fixed sites on VLDL, such as represented by apolipoproteins on the surface of the lipoprotein. The association equilibrium constants for this saturable binding at 37 °C were 7.0 (± 2.3) × 104 M-1 for R-propranolol and 9.6 (± 2.2) × 104 M-1 for S-propranolol. Comparable results were obtained at 20 °C and 27 °C for the propranolol enantiomers. This work provided fundamental information on the processes involved in the binding of R- and S-propranolol to VLDL, while also illustrating how HPAC can be used to evaluate relatively complex interactions between agents such as VLDL and drugs or other solutes. PMID:25103529

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

    PubMed Central

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

    1998-01-01

    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

  8. Low-density lipoprotein oxidation and its prevention by amidothionophosphate antioxidants.

    PubMed

    Tirosh, O; Katzhendler, J; Barenholz, Y; Kohen, R

    1999-01-01

    Amidothionophosphates (AMTPs) are a novel group of antioxidants that are lacking in pro-oxidant activity. In this paper, we compare two different amidothionophosphates: 2-hydroxy-ethyl amido, diethyl thionophosphate (AMTP-B), which contains a single primary amido group, and N,N',N-tripropylamidothionophosphate (AMTP-3A), which contains three primary amido groups. The lipoprotein/medium partition coefficients of AMTP-3A and AMTP-B are 74 and 38, respectively. Both protected isolated human low density lipoprotein (LDL) against oxidative damage induced by copper sulfate. Oxidative damage to polyunsaturated acyl chains was determined by gas chromatography (GC), and oxidation kinetics were monitored by following the accumulation of conjugated dienes spectrophotometrically at 234 nm. The AMTP antioxidants significantly protected the LDL against Cu2+-induced oxidation. However, if the LDLs were already partially oxidized, protection against oxidation by the AMTPs was reduced. AMTP-3A was more effective in protecting LDL than was AMTP-B. The difference in antioxidant activity was attributed to the 15-fold higher reactivity of AMTP-3A toward peroxides. Oxidizability of plasma lipoproteins from guinea pigs injected with AMTPs was strongly reduced.

  9. Sterol regulatory element-binding protein-1 determines plasma remnant lipoproteins and accelerates atherosclerosis in low-density lipoprotein receptor-deficient mice.

    PubMed

    Karasawa, Tadayoshi; Takahashi, Akimitsu; Saito, Ryo; Sekiya, Motohiro; Igarashi, Masaki; Iwasaki, Hitoshi; Miyahara, Shoko; Koyasu, Saori; Nakagawa, Yoshimi; Ishii, Kiyoaki; Matsuzaka, Takashi; Kobayashi, Kazuto; Yahagi, Naoya; Takekoshi, Kazuhiro; Sone, Hirohito; Yatoh, Shigeru; Suzuki, Hiroaki; Yamada, Nobuhiro; Shimano, Hitoshi

    2011-08-01

    Sterol regulatory element-binding protein-1 (SREBP-1) is nutritionally regulated and is known to be a key transcription factor regulating lipogenic enzymes. The goal of this study was to evaluate the roles of SREBP-1 in dyslipidemia and atherosclerosis. Transgenic mice that overexpress SREBP-1c in the liver and SREBP-1-deficient mice were crossed with low-density lipoprotein receptor (LDLR)-deficient mice, and the plasma lipids and atherosclerosis were analyzed. Hepatic SREBP-1c overexpression in LDLR-deficient mice caused postprandial hypertriglyceridemia, increased very-low-density lipoprotein (VLDL) cholesterol, and decreased high-density lipoprotein cholesterol in plasma, which resulted in accelerated aortic atheroma formation. Conversely, absence of SREBP-1 suppressed Western diet-induced hyperlipidemia in LDLR-deficient mice and ameliorated atherosclerosis. In contrast, bone marrow-specific SREBP-1 deficiency did not alter the development of atherosclerosis. The size of nascent VLDL particles secreted from the liver was increased in SREBP-1c transgenic mice and reduced in SREBP-1-deficient mice, accompanied by upregulation and downregulation of phospholipid transfer protein expression, respectively. Hepatic SREBP-1c determines plasma triglycerides and remnant cholesterol and contributes to atherosclerosis in hyperlipidemic states. Hepatic SREBP-1c also regulates the size of nascent VLDL particles.

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

    SciTech Connect

    Lund, H.; Takahashi, K.; Hamilton, R.L.; Havel, R.J. )

    1989-12-01

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

  11. Effects of paroxetine and sertraline on low-density lipoprotein cholesterol: an observational cohort study.

    PubMed

    Wei, Feifei; Crain, A Lauren; Whitebird, Robin R; Godlevsky, Olga V; O'Connor, Patrick J

    2009-10-01

    Antidepressant use in US adults increased 3-fold from 2.5% in 1988-94 to 8.1% in 1999-2002, based on National Health and Nutrition Examination Surveys. As the use of antidepressants increases, a comprehensive understanding of the potential health risks that may be associated with their use becomes increasingly important. This study evaluated the effects of paroxetine and sertraline on low-density lipoprotein cholesterol (LDL-C). An observational cohort study (1997-2004) of adults who had taken paroxetine or sertraline for at least 60 continuous days and had > or =2 LDL-C values measured during the study period, one while taking and one while not taking paroxetine or sertraline. A total of 13 634 LDL-C values clustered within 2682 patients were studied. We conducted mixed model regression analyses to quantify the relationship between antidepressant use and LDL-C values. The number of days taking paroxetine (beta = 0.0045; 95% CI 0.0018, 0.0073) and sertraline (beta = 0.0074; 95% CI 0.0054, 0.0093) prior to the LDL-C test were related to higher LDL-C values, after accounting for age, sex, year LDL-C was tested, co-morbidity, depression and lipid medication. The number of days that had passed since exposure to paroxetine (beta = -0.0013; 95% CI -0.0020, -0.00061) or sertraline (beta = -0.00093; 95% CI -0.016, -0.00022) were related to lower LDL-C values. The significant interaction between exposure to an antidepressant and taking a lipid medication demonstrates that the increase in LDL-C values associated with antidepressant use is ameliorated among patients who were taking a lipid medication when LDL-C was measured. Our study showed that long-term use of paroxetine or sertraline may have a measurable adverse impact on cardiovascular risk in adults. Clinical strategies should be used to address cardiovascular risk while maintaining effective treatment of major depression. In light of these findings, attention to LDL-C values should accompany antidepressant use.

  12. Low-density lipoprotein cholesterol and survival in pulmonary arterial hypertension

    PubMed Central

    Kopeć, Grzegorz; Waligóra, Marcin; Tyrka, Anna; Jonas, Kamil; Pencina, Michael J.; Zdrojewski, Tomasz; Moertl, Deddo; Stokwiszewski, Jakub; Zagożdżon, Paweł; Podolec, Piotr

    2017-01-01

    Low-density lipoprotein cholesterol(LDL-C) is a well established metabolic marker of cardiovascular risk, however, its role in pulmonary arterial hypertension (PAH) has not been determined. Therefore we assessed whether LDL-C levels are altered in PAH patients, if they are associated with survival in this group and whether pulmonary hypertension (PH) reversal can influence LDL-C levels. Consecutive 46 PAH males and 94 females were age matched with a representative sample of 1168 males and 1245 females, respectively. Cox regression models were used to assess the association between LDL-C and mortality. The effect of PH reversal on LDL-C levels was assessed in 34 patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing invasive treatment. LDL-C was lower in both PAH (2.6 ± 0.8 mmol/l) and CTEPH (2.7 ± 0.7 mmol/l) patients when compared to controls (3.2 ± 1.1 mmol/l, p < 0.001). In PAH patients lower LDL-C significantly predicted death (HR:0.44/1 mmol/l, 95%CI:0.26–0.74, p = 0.002) after a median follow-up time of 33(21–36) months. In the CTEPH group, LDL-C increased (from 2.6[2.1–3.2] to 4.0[2.8–4.9]mmol/l, p = 0.01) in patients with PH reversal but remained unchanged in other patients (2.4[2.2–2.7] vs 2.3[2.1–2.5]mmol/l, p = 0.51). We concluded that LDL-C level is low in patients with PAH and is associated with an increased risk of death. Reversal of PH increases LDL-C levels. PMID:28198422

  13. Effect of nicotinic acid administration on hepatic very low density lipoprotein-triglyceride production.

    PubMed

    Wang, W; Basinger, A; Neese, R A; Shane, B; Myong, S A; Christiansen, M; Hellerstein, M K

    2001-03-01

    Our objective was to examine very low density lipoprotein-triglyceride (VLDL-TG) kinetics after chronic and acute administration of nicotinic acid (NA). Incorporation of [1,2,3,4-(13)C(4)]palmitate and [2-(13)C(1)]glycerol into VLDL-TG was measured in five healthy, normolipidemic women. Each subject was studied twice; the 4-day hospital stays were separated by 1 mo, during which time doses of NA were increased to 2 g/day (500 mg, 4 times/day). During posttreatment study, 500 mg of NA were administered acutely at 0800. Under baseline postabsorptive conditions, incorporation curves from (13)C-labeled free fatty acid (FFA) and (13)C-labeled glycerol were superimposable, and VLDL-TG kinetics were in agreement (t(1/2) = 1.4 +/- 0.3 and 1.3 +/- 0.3 h, and production rates = 27.2 +/- 6.1 and 28.5 +/- 5.3 g/day, respectively). In the postabsorptive state after chronic NA therapy, VLDL-TG concentrations and production rates were lower despite a trend toward elevated plasma FFA concentrations and fluxes. After the acute dose of NA, plasma FFA concentrations and flux fell dramatically, and there was a virtual halt to VLDL-TG production, which continued throughout the 6-h period after NA, despite a marked rebound overshoot in serum FFA concentrations and flux after hour 2. Plasma homocysteine concentrations increased 68% (P < 0.001) in the NA phase, consistent with chronic increased transmethylation demand. We conclude that 1) NA acutely and chronically decreases VLDL-TG production rate in normal women; 2) the acute effect on VLDL-TG production is associated with an initial suppression of lipolysis but persists for several hours after the antilipolytic action of NA has abated and is observed in the basal postabsorptive state, when lipolytic rates are not reduced; and 3) the effect of NA on VLDL-TG production, therefore, cannot be completely explained by its antilipolytic actions.

  14. Low Density Lipoprotein Receptor Related Proteins as Regulators of Neural Stem and Progenitor Cell Function

    PubMed Central

    Landowski, Lila M.; Young, Kaylene M.

    2016-01-01

    The central nervous system (CNS) is a highly organised structure. Many signalling systems work in concert to ensure that neural stem cells are appropriately directed to generate progenitor cells, which in turn mature into functional cell types including projection neurons, interneurons, astrocytes, and oligodendrocytes. Herein we explore the role of the low density lipoprotein (LDL) receptor family, in particular family members LRP1 and LRP2, in regulating the behaviour of neural stem and progenitor cells during development and adulthood. The ability of LRP1 and LRP2 to bind a diverse and extensive range of ligands, regulate ligand endocytosis, recruit nonreceptor tyrosine kinases for direct signal transduction and signal in conjunction with other receptors, enables them to modulate many crucial neural cell functions. PMID:26949399

  15. Low density lipoprotein levels linkage with the periodontal status patients of coronary heart disease

    NASA Astrophysics Data System (ADS)

    Ahmad, Nafisah Ibrahim; Masulili, Sri Lelyati C.; Lessang, Robert; Radi, Basuni

    2017-02-01

    Studies found an association between periodontitis and coronary heart disease (CHD), but relationship between periodontal status CHD patients with LDL (Low Density Lipoprotein) levels, as risk factors for atherosclerosis, has not been studied. Objective: To analyze relationship between LDL and periodontal status CHD. Methods: Periodontal status of 60 CHD, 40 controls were examined (PBI, PPD, CAL) and their blood was taken to assess levels of LDL. Result: Found significant differences LDL (p=0.005), correlation between LDL with PPD (p=0.003) and CAL CHD (p=0.013), and PPD (p=0.001), CAL (p=0.008) non-CHD, but no significant correlation between LDL with PBI CAD (p=0.689) and PBI non-CHD (p=0.320). Conclusion: There is a correlation between the LDL levels with periodontal status.

  16. Antioxidant activity of thiocholesterol on copper-induced oxidation of low-density lipoprotein.

    PubMed

    Tanaka, M; Nakagawa, M

    1995-04-01

    The effect of thiocholesterol (SH-Chol) on the copper-induced in vitro oxidation of low-density lipoprotein (LDL; 1.019 < d < 1.063) was investigated. Among the antioxidants tested, including cysteine, glutathione, 2-mercaptoethanol, dithiothreitol, probucol, thiopalmitic acid, and SH-Chol, SH-Chol was the most effective antioxidant in copper-induced LDL oxidation. Also, SH-Chol completely inhibited the formation of oxysterols, i.e., 7-hydroxycholesterol and 7-ketocholesterol, in LDL particles and reduced 1,1-diphenyl-2-picrylhydrazyl used as stable free-radical model. Moreover, SH-Chol suppressed the degradation of endogenous alpha-tocopherol in LDL particles. These findings indicate that SH-Chol acts as antioxidant in the oxidative damage of LDL in vitro and as a free-radical scavenger in lipid peroxidation.

  17. Simulation of lipid peroxidation in low-density lipoprotein by a basic "skeleton" of reactions.

    PubMed

    Abuja, P M; Esterbauer, H

    1995-01-01

    A minimal kinetic model describing lipid peroxidation in low-density lipoprotein (LDL) has been set up. Models have been calculated by numeric integration of the differential equations describing this system consisting of seven reactions and eleven reactants in a single compartment. The model describes the usually observed behavior of the reaction system, showing that the crucial intermediate is the lipid peroxyl radical (LOO.). During different stages of the reaction, depending on the presence of antioxidants (alpha-tocopherol), different pathways in the reaction scheme become active. Simulation also demonstrates that tocopherol-mediated propagation can occur under certain conditions, i.e., a low rate of initiation. This, however, does not mean that tocopherol enhances lipid peroxidation in LDL, as without tocopherol the process would be much faster. Further extension of the basic model by inclusion of a hypothetical antioxidant leads to a model which is capable of describing Cu(2+)-induced LPO over the whole lag phase up to full propagation.

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

    PubMed

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

    2014-04-01

    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.

  19. Neutrophil-oxidized low density lipoprotein: generation in and clearance from the plasma.

    PubMed Central

    Görög, P.

    1992-01-01

    The prevailing concept of an extremely rapid disappearance of 'modified' low density lipoprotein (LDL) from the circulation was reinvestigated. Rabbit LDL was 'modified' by homologous activated (phagocytosing) polymorphonuclear leucocytes (PMLN), radiolabelled with a non-degradable ligand (125I-TC-LDL) and injected into rabbits. The plasma half-lives of 'modified' and native LDL were T1/2 = 2.5 and 5.75 h, respectively. Furthermore, the possibility of LDL oxidation in plasma by stimulated PMNL was investigated. Hirudin-anticoagulated human plasma was incubated with unstimulated or stimulated autologous PMNL. Chemiluminometry (reactants with microperoxidase) of the lipid extract of plasma after incubation showed lipid peroxidation to be induced by phagocytosing, but not by quiescent, leucocytes. These findings show that in plasma, stimulated leucocytes can 'modify' LDL and the circulatory half-life of the latter enables its contribution to atherogenesis. PMID:1390195

  20. 5-Lipoxygenase is not essential in macrophage-mediated oxidation of low-density lipoprotein.

    PubMed

    Jessup, W; Darley-Usmar, V; O'Leary, V; Bedwell, S

    1991-08-15

    The concentration-dependent effects of a series of lipoxygenase inhibitors and antioxidants on the macrophage-mediated oxidative modification of low-density lipoprotein (LDL) were measured. Their influence on macrophage 5-lipoxygenase pathway activity was also studied over the same concentration range. No correlation between inhibition of 5-lipoxygenase and of macrophage-mediated oxidation of LDL was observed. The capacity of the compounds to prevent cell-mediated modification of LDL could be explained in terms of their activity as either aqueous- or lipid-peroxyl radical scavengers. Two potent 5-lipoxygenase inhibitors (MK 886 and Revlon 5901), which had no radical-scavenging properties, were unable to block LDL modification. It is concluded that 5-lipoxygenase is not essential for LDL oxidation by macrophages.

  1. 5-Lipoxygenase is not essential in macrophage-mediated oxidation of low-density lipoprotein.

    PubMed Central

    Jessup, W; Darley-Usmar, V; O'Leary, V; Bedwell, S

    1991-01-01

    The concentration-dependent effects of a series of lipoxygenase inhibitors and antioxidants on the macrophage-mediated oxidative modification of low-density lipoprotein (LDL) were measured. Their influence on macrophage 5-lipoxygenase pathway activity was also studied over the same concentration range. No correlation between inhibition of 5-lipoxygenase and of macrophage-mediated oxidation of LDL was observed. The capacity of the compounds to prevent cell-mediated modification of LDL could be explained in terms of their activity as either aqueous- or lipid-peroxyl radical scavengers. Two potent 5-lipoxygenase inhibitors (MK 886 and Revlon 5901), which had no radical-scavenging properties, were unable to block LDL modification. It is concluded that 5-lipoxygenase is not essential for LDL oxidation by macrophages. PMID:1883327

  2. Counterpoint: Low-Density Lipoprotein Cholesterol Targets Are Not Needed in Lipid Treatment Guidelines.

    PubMed

    Robinson, Jennifer G; Ray, Kausik

    2016-04-01

    On the basis of accumulating evidence, low-density lipoprotein cholesterol (LDL-C) treat-to-goal approaches no longer seem to be the best way to optimize lipid-modifying therapy to prevent atherosclerotic cardiovascular disease (ASCVD). The potential for a net ASCVD risk reduction benefit is a more individualized approach to clinical decision making and may better inform patient preferences. However, risk estimation tools will need to be developed to facilitate more personalized CVD risk estimation in statin-treated patients. In the meantime, LDL-C thresholds rather than targets may aid in determining which patients might benefit from additional LDL-C-lowering therapy beyond statins. © 2016 American Heart Association, Inc.

  3. Oxidized low-density lipoprotein (Ox-LDL) impacts on erythrocyte viscoelasticity and its molecular mechanism.

    PubMed

    Wang, Xiang; Yang, Li; Liu, Yao; Gao, Wei; Peng, Weiyan; Sung, K-L Paul; Sung, Lanping Amy

    2009-10-16

    The oxidized low-density lipoprotein (Ox-LDL) plays an important role in atherosclerosis, yet it remains unclear if it damages circulating erythrocytes. In this study, erythrocyte deformability and its membrane proteins after Ox-LDL incubations are investigated by micropipette aspiration, thiol radical measurement, and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Results show that Ox-LDL incubation reduces the erythrocyte deformability, decreases free thiol radical contents in erythrocytes, and induces the cross-linking among membrane proteins. SDS-PAGE analysis reveals a high molecular weight (HMW) complex as well as new bands between spectrins and band 3 and reduced ratios between band 3 and other major membrane skeletal proteins. Analyses indicate that Ox-LDL makes erythrocytes harder to deform through a molecular mechanism by which the oxidation of free thiol radicals forms disulfide bonds among membrane skeletal proteins.

  4. Long-Term Safety and Efficacy of Lowering Low-Density Lipoprotein Cholesterol With Statin Therapy

    PubMed Central

    Ford, Ian; Murray, Heather; Packard, Chris J.

    2016-01-01

    Background— Extended follow-up of statin-based low-density lipoprotein cholesterol lowering trials improves the understanding of statin safety and efficacy. Examining cumulative cardiovascular events (total burden of disease) gives a better appreciation of the clinical value of statins. This article evaluates the long-term impact of therapy on mortality and cumulative morbidity in a high-risk cohort of men. Methods and Results— The West of Scotland Coronary Prevention Study was a primary prevention trial in 45- to 64-year-old men with high low-density lipoprotein cholesterol. A total of 6595 men were randomized to receive pravastatin 40 mg once daily or placebo for an average of 4.9 years. Subsequent linkage to electronic health records permitted analysis of major incident events over 20 years. Post trial statin use was recorded for 5 years after the trial but not for the last 10 years. Men allocated to pravastatin had reduced all-cause mortality (hazard ratio, 0.87; 95% confidence interval, 0.80–0.94; P=0.0007), attributable mainly to a 21% decrease in cardiovascular death (hazard ratio, 0.79; 95% confidence interval, 0.69–0.90; P=0.0004). There was no difference in noncardiovascular or cancer death rates between groups. Cumulative hospitalization event rates were lower in the statin-treated arm: by 18% for any coronary event (P=0.002), by 24% for myocardial infarction (P=0.01), and by 35% for heart failure (P=0.002). There were no significant differences between groups in hospitalization for noncardiovascular causes. Conclusion— Statin treatment for 5 years was associated with a legacy benefit, with improved survival and a substantial reduction in cardiovascular disease outcomes over a 20-year period, supporting the wider adoption of primary prevention strategies. PMID:26864092

  5. Modifications in low-density lipoprotein receptor expression affects Cyclosporin A cellular uptake and cytotoxicity.

    PubMed

    Leon, Carlos; Jia, Jessica; Qiu, Guosong; Hill, John S; Wasan, Kishor M

    2008-06-01

    The purpose of this study was to test the effect of modulating the expression of the human low-density lipoprotein receptor (LDLr) in human embryonic kidney (293T) cells on Cyclosporin A (CsA) cellular uptake and CsA-mediated cytotoxicity. LDLr expression was modulated using RNA interference (RNAi) and an LDLr overexpression plasmid. One of the small-interfering RNA (siRNA) constructs, LDLr-792, showed a 60% decrease in LDLr protein expression. The downregulation effect was specific as transfection with an annexin V (AxV) siRNA construct did not decrease LDLr expression levels. AxV and ABCA1 expression levels were not affected in the cells transfected with LDLr-792 (LDLr(LOW) cells) compared to the controls. At a functional level, fluorescent low-density lipoprotein (LDL) (DiI-LDL) internalization in the LDLr(LOW) cells was decreased (30%) compared to control cells. We tested the dose-dependent cytotoxicity induced by CsA using a respiration assay. We found a decrease in CsA-mediated cytotoxicity in the range of CsA doses studied (1-10 microg/mL) in the LDLr(LOW) cells compared to the pSHAG-transfected cells, reaching a statistical significance at 10 microg/mL CsA. At higher CsA doses we found a significant decrease in LDLr expression. When the control and LDLr(LOW) cells were treated with another cytotoxic drug, gentamycin, there was no difference in the cell viability, suggesting that this effect is specific for CsA. We confirmed the association of LDLr expression levels with CsA uptake by overexpressing the LDLr. The LDLr overexpressing cells showed an enhanced uptake of radiolabelled CsA. Taken together these results suggest that CsA internalization and cytotoxicity are affected by the LDL receptor expression levels.

  6. Relationship between oxidized low-density lipoprotein antibodies and obesity in different glycemic situations

    PubMed Central

    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

    2014-01-01

    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

  7. Oxidative modification of low-density lipoprotein and atherogenetic risk in beta-thalassemia.

    PubMed

    Livrea, M A; Tesoriere, L; Maggio, A; D'Arpa, D; Pintaudi, A M; Pedone, E

    1998-11-15

    We investigated the oxidative state of low-density lipoprotein (LDL) in patients with beta-thalassemia to determine whether there was an association with atherogenesis. Conjugated diene lipid hydroperoxides (CD) and the level of major lipid antioxidants in LDL, as well as modified LDL protein, were evaluated in 35 beta-thalassemia intermedia patients, aged 10 to 60, and compared with age-matched healthy controls. Vitamin E and beta-carotene levels in LDL from patients were 45% and 24% of that observed in healthy controls, respectively. In contrast, the mean amount of LDL-CD was threefold higher and lysil residues of apo B-100 were decreased by 17%. LDL-CD in thalassemia patients showed a strong inverse correlation with LDL vitamin E (r = -0.784; P <.0001), while a negative trend was observed with LDL-beta-carotene (r = -0.443; P =.149). In the plasma of thalassemia patients, malondialdehyde (MDA), a byproduct of lipid peroxidation, was increased by about twofold, while vitamin E showed a 52% decrease versus healthy controls. LDL-CD were inversely correlated with plasma vitamin E (r = -0.659; P <.0001) and correlated positively with plasma MDA (r = 0.621; P <. 0001). Plasma ferritin was positively correlated with LDL-CD (r = 0.583; P =.0002). No correlation was found between the age of the patients and plasma MDA or LDL-CD. The LDL from thalassemia patients was cytotoxic to cultured human fibroblasts and cytotoxicity increased with the content of lipid peroxidation products. Clinical evidence of mild to severe vascular complications in nine of the patients was then matched with levels of LDL-CD, which were 36% to 118% higher than the mean levels of the patients. Our results could account for the incidence of atherogenic vascular diseases often reported in beta-thalassemia patients. We suggest that the level of plasma MDA in beta-thalassemia patients may represent a sensitive index of the oxidative status of LDL in vivo and of its potential atherogenicity.

  8. Atorvastatin Restores Endothelial Function in Normocholesterolemic Smokers Independent of Changes in Low-Density Lipoprotein

    PubMed Central

    Beckman, Joshua A.; Liao, James K.; Hurley, Shauna; Garrett, Leslie A.; Chui, Daoshan; Mitra, Debi; Creager, Mark A.

    2009-01-01

    Cigarette smoking impairs endothelial function. Hydroxymethylglutaryl (HMG) CoA reductase inhibitors (statins) may favorably affect endothelial function via nonlipid mechanisms. We tested the hypothesis that statins would improve endothelial function independent of changes in lipids in cigarette smokers. Twenty normocholesterolemic cigarette smokers and 20 matched healthy control subjects were randomized to atorvastatin 40 mg daily or placebo for 4 weeks, washed out for 4 weeks, and then crossed-over to the other treatment. Baseline low-density lipoprotein (LDL) levels were similar in smokers and healthy subjects, 103±22 versus 95±27 mg/dL, respectively (P=NS) and were reduced similarly in smokers and control subjects by atorvastatin, to 55±30 and 58±20 mg/dL, respectively (P=NS). Vascular ultrasonography was used to determine brachial artery, flow-mediated, endothelium-dependent, and nitroglycerin-mediated, endothelium-independent vasodilation. To elucidate potential molecular mechanisms that may account for changes in endothelial function, skin biopsy specimens were assayed for eNOS mRNA, eNOS activity, and nitrotyrosine. Endothelium-dependent vasodilation was less in smokers than nonsmoking control subjects during placebo treatment, 8.0±0.6% versus 12.1±1.1%, (P=0.003). Atorvastatin increased endothelium-dependent vasodilation in smokers to 10.5±1.3% (P=0.017 versus placebo) but did not change endothelium-dependent vasodilation in control subjects (to 11.0±0.8%, P=NS). Endothelium-independent vasodilation did not differ between groups during placebo treatment and was not significantly affected by atorvastatin. Multivariate analysis did not demonstrate any association between baseline lipid levels or the change in lipid levels and endothelium-dependent vasodilation. Cutaneous nitrotyrosine levels and skin microvessel eNOS mRNA, but not ENOS activity, were increased in smokers compared with controls but unaffected by atorvastatin treatment. Atorvastatin

  9. Effects of oxidized low density lipoprotein on transformation of valvular myofibroblasts to osteoblast-like phenotype.

    PubMed

    Chen, Di; Shen, Ying-Lian; Hu, Wei-Lin; Chen, Zheng-Ping; Li, Yong-Sheng

    2015-06-01

    In order to investigate the roles of Wnt signal pathway in transformation of cardiac valvular myofibroblasts to the osteoblast-like phenotype, the primary cultured porcine aortic valve myofibroblasts were incubated with oxidized low density lipoprotein (ox-LDL, 50 mg/L), and divided into four groups according to the ox-LDL treatment time: control group, ox-LDL 24-h group, ox-LDL 48-h group, and ox-LDL 72-h group. Wnt signal pathway blocker Dickkopf-1 (DDK-1, 100 μg/L) was added in ox-LDL 72-h group. The expression of a-smooth muscle actin (α-SMA), bone morphogenetic protein 2 (BMP2), alkaline phosphatase (ALP), and osteogenic transcription factor Cbfa-1 was detected by Western blotting, and that of β-catenin, a key mediator of Wnt signal pathway by immunocytochemical staining method. The Wnt/β-catenin was observed and the transformation of myofibroblasts to the osteoblast-like phenotype was examined. The expression of α-SMA, BMP2, ALP and Cbfa-1 proteins in the control group was weaker than in the ox-LDL-treated groups. In ox-LDL-treated groups, the protein expression of a-SMA, BMP2, ALP, and Cbfa-1 was significantly increased in a time-dependent manner as compared with the control group, and there was significant difference among the three ox-LDL-treated groups (P<0.05 for all); β-catenin protein was also up-regulated in the ox-LDL-treated groups in a time-dependent manner as compared with the control group (P<0.05), and its transfer from cytoplasm to nucleus and accumulation in the nucleus were increased in the same fashion (P<0.05). After addition of DKK-1, the expression of α-SMA, bone-related proteins and β-catenin protein was significantly reduced as compared with ox-LDL 72-h group (P<0.05). The Wnt/ β-catenin signaling pathway may play an important role in transformation of valvular myofibroblasts to the osteoblast-like phenotype.

  10. The Relationship of Plasma miR-29a and Oxidized Low Density Lipoprotein with Atherosclerosis.

    PubMed

    Huang, Yu-Qing; Cai, An-Ping; Chen, Ji-Yan; Huang, Cheng; Li, Jie; Feng, Ying-Qing

    2016-01-01

    Atherosclerosis is a chronic inflammatory condition associated with a variety of vascular diseases. Previous studies showed that both miR-29a and oxidized low density lipoprotein (ox-LDL) were vital in the development of atherosclerosis. However, the relationship between miR-29a and ox-LDL remains unknown. This study was designed to investigate the association of miR-29a and ox-LDL and to test whether circulating miR-29a and ox-LDL levels could predict atherosclerosis. In 170 participants, plasma levels of miR-29a were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) while plasma ox-LDL levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. The relationship between miR-29a level and ox-LDL and carotid intima-media thickness (cIMT) was assessed using the Spearman correlation coefficient and multiple liner regression. Compared with the normal cIMT group, the increased cIMT group had higher levels of ox-LDL (0.47 ± 0.08 vs 0.29 ± 0.06 ng/ml, p = 0.003) and miR-29a (32.93 ± 4.26 vs 26.37 ± 1.04, p < 0.001). A positive correlation was found between ox-LDL and miR-29a (r = 0.695, p < 0.001), and both the ox-LDL (r = 0.857, p < 0.001) and the miR-29a (r = 0.753, p < 0.001) were positively related to cIMT. Furthermore, multiple liner regression indicated that a significant correlation between ox-LDL and cIMT (β = 0.768, p < 0.001), as well as between miR-29a and cIMT (β = 0.686, p <0.001). The combination of miR-29a and ox-LDL (AUC = 0.926, p < 0.001) offered a better predictive value for atherosclerosis than either miR-29a (AUC = 0.759, p < 0.001) or ox-LDL (AUC = 0.762, p < 0.001) alone. Increased miR-29a and ox-LDL levels were associated with an early stage of atherosclerosis, and the combination of miR-29a and ox-LDL offered better predictive values for atherosclerosis than either alone. © 2016 The Author(s) Published by S. Karger AG, Basel.

  11. Peroxisome proliferator-activated receptor-γ regulates the expression and function of very-low-density lipoprotein receptor

    PubMed Central

    Tao, Huan; Aakula, Srikanth; Abumrad, Naji N.

    2010-01-01

    Very-low-density lipoprotein receptor (VLDLR) is a member of the low-density receptor family, highly expressed in adipose tissue, heart, and skeletal muscle. It binds apolipoprotein E-triglyceride-rich lipoproteins and plays a significant role in triglyceride metabolism. PPARγ is a primary regulator of lipid metabolism in adipocytes and controls the expression of an array of genes involved in lipid trafficking in adipocytes. However, it is not known whether VLDLR is also under the control of PPARγ. In this study, we investigated the role of PPARγ in the regulation of VLDLR expression and function in vivo and in vitro. During the differentiation of 3T3-L1 preadipocytes, the levels of VLDLR protein and mRNA increased in parallel with the induction of PPARγ expression and reached maximum in mature adipocytes. Treatment of differentiated adipocytes with PPARγ agonist pioglitazone upregulated VLDLR expression in dose- and time-dependent manners. In contrast, specific inhibition of PPARγ significantly downregulated the protein level of VLDLR. Induction of VLDLR is also demonstrated in vivo in adipose tissue of wild-type (WT) mice treated with pioglitazone. In addition, pioglitazone increased plasma triglyceride-rich lipoprotein clearance and increased epididymal fat mass in WT mice but failed to induce similar effects in vldlr−/− mice. These results were further corroborated by the finding that pioglitazone treatment enhanced adipogenesis and lipid deposition in preadipocytes of WT mice, while its effect in VLDLR-null preadipocytes was significantly blunted. These findings provide direct evidence that VLDLR expression is regulated by PPARγ and contributes in lipid uptake and adipogenesis. PMID:19861583

  12. High hydrostatic pressure specifically affects molecular dynamics and shape of low-density lipoprotein particles

    PubMed Central

    Golub, M.; Lehofer, B.; Martinez, N.; Ollivier, J.; Kohlbrecher, J.; Prassl, R.; Peters, J.

    2017-01-01

    Lipid composition of human low-density lipoprotein (LDL) and its physicochemical characteristics are relevant for proper functioning of lipid transport in the blood circulation. To explore dynamical and structural features of LDL particles with either a normal or a triglyceride-rich lipid composition we combined coherent and incoherent neutron scattering methods. The investigations were carried out under high hydrostatic pressure (HHP), which is a versatile tool to study the physicochemical behavior of biomolecules in solution at a molecular level. Within both neutron techniques we applied HHP to probe the shape and degree of freedom of the possible motions (within the time windows of 15 and 100 ps) and consequently the flexibility of LDL particles. We found that HHP does not change the types of motion in LDL, but influences the portion of motions participating. Contrary to our assumption that lipoprotein particles, like membranes, are highly sensitive to pressure we determined that LDL copes surprisingly well with high pressure conditions, although the lipid composition, particularly the triglyceride content of the particles, impacts the molecular dynamics and shape arrangement of LDL under pressure. PMID:28382948

  13. Lipid Composition Influences the Shape of Human Low-Density Lipoprotein in Vitreous Ice

    PubMed Central

    Coronado-Gray, Andrea; van Antwerpen, Rik

    2005-01-01

    Earlier cryo-electron microscopic studies have indicated that the normal low-density lipoprotein (N-LDL) has a discoid shape when its core is in the liquid-crystalline state. In the present study, we investigated whether the shape of LDL depends on the physical state and/or the lipid composition of the lipoprotein core. Using a custom-built freezing device, we vitrified N-LDL samples from either above or below the phase-transition temperature of the core (42°C and 24°C, respectively). Cryo-electron microscopy revealed no differences between these samples and indicated a discoid shape of the N-LDL particle. In contrast, triglyceride-enriched LDL (T-LDL) did not have discoid features and appeared to be quasi-spherical in preparations that were vitrified from either 42°C or 24°C. These results suggest that the shape of N-LDL is discoid, regardless of the physical state of its core, while T-LDL is more spherical. Aspects that may influence the shape of LDL are discussed. PMID:16094859

  14. High hydrostatic pressure specifically affects molecular dynamics and shape of low-density lipoprotein particles

    NASA Astrophysics Data System (ADS)

    Golub, M.; Lehofer, B.; Martinez, N.; Ollivier, J.; Kohlbrecher, J.; Prassl, R.; Peters, J.

    2017-04-01

    Lipid composition of human low-density lipoprotein (LDL) and its physicochemical characteristics are relevant for proper functioning of lipid transport in the blood circulation. To explore dynamical and structural features of LDL particles with either a normal or a triglyceride-rich lipid composition we combined coherent and incoherent neutron scattering methods. The investigations were carried out under high hydrostatic pressure (HHP), which is a versatile tool to study the physicochemical behavior of biomolecules in solution at a molecular level. Within both neutron techniques we applied HHP to probe the shape and degree of freedom of the possible motions (within the time windows of 15 and 100 ps) and consequently the flexibility of LDL particles. We found that HHP does not change the types of motion in LDL, but influences the portion of motions participating. Contrary to our assumption that lipoprotein particles, like membranes, are highly sensitive to pressure we determined that LDL copes surprisingly well with high pressure conditions, although the lipid composition, particularly the triglyceride content of the particles, impacts the molecular dynamics and shape arrangement of LDL under pressure.

  15. High hydrostatic pressure specifically affects molecular dynamics and shape of low-density lipoprotein particles.

    PubMed

    Golub, M; Lehofer, B; Martinez, N; Ollivier, J; Kohlbrecher, J; Prassl, R; Peters, J

    2017-04-06

    Lipid composition of human low-density lipoprotein (LDL) and its physicochemical characteristics are relevant for proper functioning of lipid transport in the blood circulation. To explore dynamical and structural features of LDL particles with either a normal or a triglyceride-rich lipid composition we combined coherent and incoherent neutron scattering methods. The investigations were carried out under high hydrostatic pressure (HHP), which is a versatile tool to study the physicochemical behavior of biomolecules in solution at a molecular level. Within both neutron techniques we applied HHP to probe the shape and degree of freedom of the possible motions (within the time windows of 15 and 100 ps) and consequently the flexibility of LDL particles. We found that HHP does not change the types of motion in LDL, but influences the portion of motions participating. Contrary to our assumption that lipoprotein particles, like membranes, are highly sensitive to pressure we determined that LDL copes surprisingly well with high pressure conditions, although the lipid composition, particularly the triglyceride content of the particles, impacts the molecular dynamics and shape arrangement of LDL under pressure.

  16. Familial hypercholesterolemia in a rhesus monkey pedigree: molecular basis of low density lipoprotein receptor deficiency.

    PubMed Central

    Hummel, M; Li, Z G; Pfaffinger, D; Neven, L; Scanu, A M

    1990-01-01

    We have recently identified a family of rhesus monkeys with members exhibiting a spontaneous hypercholesterolemia associated with a low density lipoprotein receptor (LDLR) deficiency. By using the polymerase chain reaction, we now show that the affected monkeys are heterozygous for a nonsense mutation in exon 6 of the LDLR gene. This mutation changes the sequence of the codon for amino acid 284 (tryptophan) from TGG to TAG, thereby generating a nonsense codon potentially resulting in a truncated 283-amino acid protein, which needs documentation, however. This G----A mutation also creates a site for the restriction endonuclease Spe I. Using this site as a marker for this nonsense mutation, we have shown that the mutation is present in all of the affected members of the pedigree and absent in unaffected members and that the mutation segregates with the phenotype of spontaneous hypercholesterolemia through three generations. Quantitative analyses of RNA obtained from liver biopsies show that the abundance of the LDLR RNA is also reduced by about 50%. Thus, we have identified a primate model for human familial hypercholesterolemia which will be useful for studying the relationship between the LDLR and lipoprotein metabolism and for assessing the efficacy of diets and drugs in the treatment of human familial hypercholesterolemia. Images PMID:2326270

  17. Metabolic imaging with gallium-68- and indium-111-labeled low-density lipoprotein

    SciTech Connect

    Moerlein, S.M.; Daugherty, A.; Sobel, B.E.; Welch, M.J. )

    1991-02-01

    Low-density lipoprotein (LDL) labeled with either gallium-68 ({sup 68}Ga) or indium-111 ({sup 111}In) was evaluated as a potential PET or SPECT radiopharmaceutical for determination of hepatic lipoprotein metabolism in rabbits. Gallium-68 or {sup 111}In was linked to LDL via diethylenetriaminepentaacetic acid (DTPA) with a 25-70% radiochemical yield. Studies in vivo that compared {sup 68}Ga- or {sup 111}In-DTPA-LDL with dilactitol-({sup 125}I)-tyramine LDL and 131I-LDL showed that both {sup 68}Ga- and {sup 111}In-labeled LDL behaved as residualizing radiotracers. Localization of radioactivity within the liver of normal rabbits was visualized clearly with ({sup 68}Ga)DTPA-LDL by PET and with ({sup 111}In)DTPA-LDL by gamma scintigraphy. Significant differences were observed in hepatic uptake of normal compared with hypercholesterolemic rabbits in which low-capacity LDL receptor-mediated catabolism was saturated. Gallium-68 and {sup 111}In-DTPA-LDL are attractive radiopharmaceuticals for noninvasive delineation of tissue LDL metabolism under normal and pathophysiologic conditions.

  18. Marked effects of extreme levels of lipoprotein(a) on estimation of low-density lipoprotein cholesterol.

    PubMed

    Saeedi, Ramesh; Li, Min; Allard, Matt; Frohlich, Jiri

    2014-08-01

    Low-density lipoprotein cholesterol (LDL-C) is usually calculated using the Friedewald equation. However, this calculation method does not account for the cholesterol associated with lipoprotein(a) [Lp(a)]. Using the Dahlen equation, Li et al. have shown a strong positive correlation between serum Lp(a) levels and overestimation of LDL-C levels. To determine how the extreme levels of Lp(a) influence the LDL-C calculation. We performed a retrospective chart review of the lipid profile and Lp(a) of 223 patients (men and women). LDL-C was calculated using the Friedewald equation. Lp(a) concentrations were measured by an ELISA. Other serum lipids were measured enzymatically by standard methodology. Corrected LDL-C was calculated using the Dahlen equation. We found that this overestimation is very significant in individuals with extreme levels of Lp(a) (mean overestimation of 40% at Lp(a) >1200mg/L). Calculated LDL-C is markedly overestimated in patients with extreme levels of Lp(a). Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  19. The affection of the disturbance of the hydrodynamics of blood in case of stress on pathological increase of level of low density lipoproteins in blood. The formation of cylindrical plaques, and their participation in the development of acute ischemic disorders of heart and brain.

    PubMed

    Rusanov, S E

    2017-09-01

    In this article is given the new insight about the affection of stress on the increase of level of low density lipoproteins (LDL) in the blood, which is connected with the disturbance of hydrodynamics in the bloodstream, the attention was paid to the cylindrical cholesterol plaque, and it's classification. The disturbance of hydrodynamics of blood under the stress leads to the formation of a cylindrical cholesterol plaque, which repeats the contour of the vessel, and leads to the ischemic disorders of the heart and brain. The cylindrical cholesterol plaque goes through several stages of development: friable, yielding, dense, old. In the case of destruction of friable, fresh cholesterol plaque, releases a big quantity of low-density lipoproteins. This leads to the pathological increase of level of LDL in the blood. In the case of long disturbance of hydrodynamics, occurs the formation of strong links between low-density lipoproteins. Yielding cholesterol plaque is formed. Further maturation of cylindrical cholesterol plaque, leads to it's densifying and damage. We may emphasize, that short periods of strong contraction and expansion of vessels lead to the increase of level of LDL in the blood. Self-dependent restoration of normal level of LDL in blood occurs in the case of restoration of pressure in the limits of numbers, which are specific for particular person, and which don't exceed the physiological standard. Among patients with long duration of stress, the duration of vasospasm increases. LDL, without having a possibility to crumble, begin to stick together and form the yielding cylindrical plaque. It is characterized by having of not so strong connection with the vascular wall, and maintains only at the expanse of iteration of the vascular wall, it has cylindrical shape, is elastic and yellow. The thickness and length of walls depends on the degree of cross-clamping during the time of formation of yielding cylindrical plaque. In the case of stopping of spasm

  20. Mipomersen preferentially reduces small low-density lipoprotein particle number in patients with hypercholesterolemia.

    PubMed

    Santos, Raul D; Raal, Frederick J; Donovan, Joanne M; Cromwell, William C

    2015-01-01

    Because of variability in lipoprotein cholesterol content, low-density lipoprotein (LDL) cholesterol frequently underrepresents or overrepresents the number of LDL particles. Mipomersen is an antisense oligonucleotide that reduces hepatic production of apolipoprotein B-100, the sole apolipoprotein of LDL. To characterize the effects of mipomersen on lipoprotein particle numbers as well as subclass distribution using nuclear magnetic resonance (NMR) spectroscopy. We compared the tertiary results for the direct measurement of LDL particle numbers by NMR among 4 placebo-controlled, phase 3 studies of mipomersen that had similar study designs but different patient populations: homozygous familial hypercholesterolemia (HoFH), severe hypercholesterolemia, heterozygous familial hypercholesterolemia with established coronary artery disease, or hypercholesterolemia with high risk for coronary heart disease (HC-CHD). HoFH patients had the highest median total LDL particles at baseline compared with HC-CHD patients, who had the lowest. At baseline, the HoFH population uniquely had a greater mean percentage of large LDL particles (placebo, 60.2%; mipomersen, 54.9%) compared with small LDL particles (placebo, 33.1%; mipomersen, 38.9%). In all 4 studies, mipomersen was associated with greater reductions from baseline in the concentrations of small LDL particles compared with those of large LDL particles, and both total LDL particles and small LDL particles were statistically significantly reduced. Mipomersen consistently reduced all LDL particle numbers and preferentially reduced the concentration of small LDL particles in all 4 phase 3 studies. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  1. Oyster mushroom (Pleurotus ostreatus) reduces the production and secretion of very low density lipoproteins in hypercholesterolemic rats.

    PubMed

    Bobek, P; Ozdin, L

    1996-09-01

    Oyster mushroom (Pleurotus ostreatus) reduced the production and secretion of nascent very low density lipoproteins in hypercholesterolemic rats. In male Wistar rats (initial body weight about 70 g) fed a semisynthetic diet with 0.3% of cholesterol, the addition of 5% of powdered oyster mushroom (Pleurotus ostreatus) to the diet reduced after 8 weeks the level of serum cholesterol (by 36%) and accumulation of cholesterol and triglycerides in liver (by 51 and 32%, respectively). The decreased levels of serum cholesterol were caused to the same extent by reduction of cholesterol content in very low density lipoproteins (VLDL) and in low density lipoproteins (LDL) (by 53 and 47%, respectively). Biosynthesis of all structural lipids of VLDL (phospholipids, cholesterol, triglycerides) in liver and incorporation of de novo synthesized lipids into secreted nascent VLDL (measured by simultaneous application of Na-acetate-1-14 C and Triton WR 1339 which inhibits peripheral lipolysis) was reduced by application of diet with oyster mushroom.

  2. Effect of human Apo AIV against lipid peroxidation of very low density lipoproteins.

    PubMed

    Ferretti, G; Bacchetti, T; Bicchiega, V; Curatola, G

    2002-01-01

    Recent studies have demonstrated that Apo AIV exerts a protective effect against atherosclerosis. Moreover, Qin et al. (Am. J. Physiol. 274 (1998) H1836) have demonstrated that Apo AIV, isolated from rat plasma, exerts an inhibitory effect against Cu(2+)-induced lipid peroxidation of intestinal lymph and LDL. The aim of the study was to investigate whether human Apo AIV exerts a protective effect against Cu(2+)-induced lipid peroxidation. Our results demonstrated that human Apo AIV exerted an inhibitory effect against Cu(2+) and AAPH induced lipid peroxidation of VLDL, as shown by the lower increase in the levels of TBARS and conjugated dienes in lipoproteins preincubated with Apo AIV. In addition, the tryptophan (Trp) and probe 2-(dimethylamino)-6-lauroylnaphthalene (Laurdan) fluorescence studies demonstrated that the modifications of spectral properties in both lipoproteins preincubated with Apo AIV were lower with respect to ox-lipoproteins, suggesting that Apo AIV prevents the modification of physico-chemical properties due to peroxidation.

  3. Ethanol extract of propolis protects endothelial cells from oxidized low density lipoprotein-induced injury by inhibiting lectin-like oxidized low density lipoprotein receptor-1-mediated oxidative stress.

    PubMed

    Fang, Yongqi; Li, Jinguo; Ding, Mingde; Xu, Xiaoyan; Zhang, Jiajun; Jiao, Peng; Han, Ping; Wang, Jiafu; Yao, Shutong

    2014-12-01

    Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), as the primary oxidized low-density lipoprotein (ox-LDL) receptor on endothelial cells, plays a crucial role in endothelial injury, which is a driving force in the initiation and development of atherosclerosis. Our previous studies have shown that ethanol extract of propolis (EEP) promotes reverse cholesterol transport and inhibits atherosclerotic lesion development. However, the protective effects of EEP against ox-LDL-induced injury in endothelial cells and the underlying mechanisms are still unknown. This study was designed to test the hypothesis that EEP attenuates ox-LDL-induced endothelial oxidative injury via modulation of LOX-1-mediated oxidative stress. Our results showed that exposure of human umbilical vein endothelial cells (HUVECs) to ox-LDL (100 mg/L) led to the decrease in cell viability and increase in lactate dehydrogenase (LDH) release, caspase-3 activation, and apoptosis, whereas pretreatment with EEP (7.5, 15 and 30 mg/L) protected against such damages in a dose-dependent manner. In addition, EEP mitigated ox-LDL uptake by HUVECs and attenuated ox-LDL-upregulated LOX-1 expression both at the mRNA and protein levels. Moreover, EEP suppressed the ox-LDL-induced oxidative stress as assessed by decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, reactive oxygen species (ROS), and malondialdehyde (MDA) generation as well as increased antioxidant enzyme activities. Similar results were observed in the anti-LOX-1 antibody or diphenyleneiodonium (DPI)-pretreated HUVECs. These data indicate that EEP may protect HUVECs from ox-LDL-induced injury and that the mechanism at least partially involves its ability to inhibit endothelial LOX-1 upregulation and subsequent oxidative stress.

  4. Studies on epitopes on low-density lipoprotein modified by 4-hydroxynonenal. Biochemical characterization and determination.

    PubMed Central

    Chen, Q; Esterbauer, H; Jürgens, G

    1992-01-01

    Oxidation of human low-density lipoprotein (LDL) was found to be accompanied by the generation of various reactive aldehydes. One of them, 4-hydroxynonenal (HNE), was shown to modify LDL to a form which represents a good model of oxidized LDL (ox-LDL). In order to investigate the epitopes newly formed on HNE-modified LDL, a polyvalent antiserum to HNE-LDL [anti-(HNE-LDL)] was raised in rabbits and the non-specific components were removed with native LDL coupled to CNBr-Sepharose 4B. Competitive fluorescence immunoassay analysis showed that anti-(HNE-LDL) recognized HNE-LDL, copper-oxidized LDL, HNE-albumin and to a lower extent HNE-modified high-density lipoprotein 3 (HNE-HDL3) and ox-HDL3 but not native LDL. A certain degree of cross-reactivity of the antibody with LDLs modified by either hexanal or 2,4-heptadienal was found. No reaction was obtained with LDL labelled with malondialdehyde. From the abilities of HNE-modified poly(L-amino acids) to compete with HNE-LDL for binding to anti-(HNE-LDL), it is postulated that lysine, tyrosine, arginine and histidine are involved in the formation of HNE-derived epitopes on apolipoprotein B (apo B). Using a double-sandwich fluorescence immunoassay [capture antibody: anti-(apo B); detection antibody: anti-(HNE-LDL)] we found that the HNE-derived epitopes were expressed at a far higher degree in ox-LDL and HNE-LDL than in native LDL. PMID:1280111

  5. Highly absorptive curcumin reduces serum atherosclerotic low-density lipoprotein levels in patients with mild COPD.

    PubMed

    Funamoto, Masafumi; Sunagawa, Yoichi; Katanasaka, Yasufumi; Miyazaki, Yusuke; Imaizumi, Atsushi; Kakeya, Hideaki; Yamakage, Hajime; Satoh-Asahara, Noriko; Komiyama, Maki; Wada, Hiromichi; Hasegawa, Koji; Morimoto, Tatsuya

    2016-01-01

    COPD is mainly caused by tobacco smoking and is associated with a high frequency of coronary artery disease. There is growing recognition that the inflammation in COPD is not only confined to the lungs but also involves the systemic circulation and can impact nonpulmonary organs, including blood vessels. α1-antitrypsin-low-density lipoprotein (AT-LDL) complex is an oxidatively modified LDL that accelerates atherosclerosis. Curcumin, one of the best-investigated natural products, is a powerful antioxidant. However, the effects of curcumin on AT-LDL remain unknown. We hypothesized that Theracurmin(®), a highly absorptive curcumin with improved bioavailability using a drug delivery system, ameliorates the inflammatory status in subjects with mild COPD. This is a randomized, double-blind, parallel-group study. Subjects with stages I-II COPD according to the Japanese Respiratory Society criteria were randomly assigned to receive 90 mg Theracurmin(®) or placebo twice a day for 24 weeks, and changes in inflammatory parameters were evaluated. There were no differences between the Theracurmin(®) and placebo groups in terms of age, male/female ratio, or body mass index in 39 evaluable subjects. The percent changes in blood pressure and hemoglobin A1c and LDL-cholesterol, triglyceride, or high-density lipoprotein-cholesterol levels after treatment were similar for the two groups. However, the percent change in the AT-LDL level was significantly (P=0.020) lower in the Theracurmin(®) group compared with the placebo group. Theracurmin(®) reduced levels of atherosclerotic AT-LDL, which may lead to the prevention of future cardiovascular events in mild COPD subjects.

  6. Low-density lipoprotein cholesterol: association with mortality and hospitalization in hemodialysis patients.

    PubMed

    Chiang, Chih-Kang; Ho, Tai-I; Hsu, Shih-Ping; Peng, Yu-Sen; Pai, Mei-Fen; Yang, Shao-Yu; Hung, Kuan-Yu; Tsai, Tun-Jun

    2005-01-01

    Hypocholesterolemia is a common finding in hospitalized elderly people, critically ill surgical patients, septic patients and end-stage renal disease patients. The different effect of lipid subfractions on patients with end-stage renal disease has never been demonstrated. We aim to study the effect of lipid subfractions on hospitalization and mortality in maintenance hemodialysis (MHD) patients. Lipid subfractions, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were measured in 210 patients with MHD in a single dialysis center. Patients were stratified into three groups based on the tertiles of lipid levels, and differences in patient characteristics and survival were evaluated. Of a total of 22 deceased patients in our MHD cohort, infection-related mortality (50%) was higher than cardiovascular-related mortality (18.2%). Significant differences (p < 0.05) in the duration and frequency of hospitalization and in mortality events were observed when patients were divided into different subgroups according to the tertiles of baseline TC and LDL-C levels. Patients with lower LDL had significantly lower levels of albumin, TC and TG. The LDL-C tertiles were similar in terms of age, hypertension, diabetes, biochemical results, hematocrit, adequacy of hemodialysis and normalized protein catabolism rate. Both TC and LDL-C predicted survival (p < 0.001), but not TG and HDL-C in the Kaplan-Meier model. The Cox proportional hazard model demonstrated that baseline serum LDL-C was the best lipid subfraction in predicting all-cause death with an adjusted hazard ratio (95% confidence interval) for each 10 mg/dl of 0.752 (0.631-0.898; p = 0.002). We firstly demonstrated that lipid subfractions, including TC and LDL-C, predict poor outcomes in a MHD cohort with high infection-related mortality.

  7. Structure of human plasma low-density lipoproteins: molecular organization of the central core.

    PubMed Central

    Atkinson, D; Deckelbaum, R J; Small, D M; Shipley, G G

    1977-01-01

    Human plasma low density lipoprotein (LDL) exhibits a thermal transition over the temperature range 20-40 degrees. This transition is associated with a structural change within the lipoprotein particle and is reflected in the small-angle x-ray scattering profiles from LDL. The scattering profile of the quasispherical LDL particle at 10 degrees shows a relatively intense maximum at 1/36 A-1 which is absent from the scattering of LDL at 45 degrees. Theoretical calculations, using model electron density distributions, have been carried out to describe the packing of arrangement of the cholesterol esters, based on perturbations of the molecular packing of crystalline cholesteryl myristate, adequately reproduces the high relative intensity of the x-ray scattering maximum at 1/36 A-1. The perturbations of the packing in the crystal structure of cholesteryl myristate involve "melting" of the hydrocarbon chains of the esters together with translations of pairs of molecules parallel to the molecular long axis. The interaction of opposing steroid moieties, with C18 and C19 angular methyl groups interlocked, exhibited in the crystal structure is retained in the perturbed arrangement. At 45 degrees, thermally induced disorder of this arrangement averages the electron density of the central core. The x-ray scattering profiles of particles with a homogeneous electron density in the core region do not show a high relative intensity of the subsidiary maxima in the 1/36 A-1 region, in agreement with experimental observation. The results of these calculations support the concept that the thermal transition observed for LDL is due to a smectic leads to disordered transition of the cholesterol esters in the core of the LDL particle. PMID:191827

  8. Influence of native and hypochlorite-modified low-density lipoprotein on gene expression in human proximal tubular epithelium.

    PubMed

    Porubsky, Stefan; Schmid, Holger; Bonrouhi, Mahnaz; Kretzler, Matthias; Malle, Ernst; Nelson, Peter J; Gröne, Hermann-Josef

    2004-06-01

    Inflammatory infiltrates can modify (lipo)proteins via hypochlorous acid/hypochlorite (HOCl/OCl(-)) an oxidant formed by the myeloperoxidase-H(2)O(2)-halide system. These oxidatively modified proteins emerge in tubuli in some proteinuric and interstitial diseases. Human proximal tubular cells (HK-2) were used to confirm the hypothesis of detrimental and differential impact of HOCl-modified low density lipoprotein (HOCl-LDL), an in vivo occurring lipoprotein modification exerting proatherogenic and proinflammatory capacity. HOCl-LDL showed dose-dependent antiproliferative effects in HK-2 cells. Small dedicated cDNA macroarrays were used to identify differentially regulated genes. A rapid increase in the expression of genes involved in reactive oxygen species metabolism and cell stress, eg, heme oxygenase-1, thioredoxin reductase, cytochrome b5 reductase, Gadd 153, amino acid transporter E16, and HSP70 was found after HOCl-LDL treatment of HK-2 cells. In parallel, genes involved in tissue remodeling and inflammation eg, CTGF, VCAM-1, IL-1beta, MMP7, and VEGF were up-regulated. Quantitative RT-PCR verified differential expression of a subset of these genes in microdissected tubulointerstitia from patients with acute tubular damage, progressive proteinuric renal disease, and membranous glomerulonephritis (with declining renal function), but not in stable patients with proteinuria caused by minimal change disease. The demonstration of selective up-regulation of a subgroup of genes if proteinuria is accompanied by the presence of HOCl-modified (lipo)proteins support the potential pathophysiological role of the myeloperoxidase-H(2)O(2)-halide system and HOCl-LDL in renal disease.

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

    PubMed Central

    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

    2009-01-01

    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-γ and tumor necrosis factor-α 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-γ- and tumor necrosis factor-α-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

  10. Mechanobiology of low-density lipoprotein transport within an arterial wall--impact of hyperthermia and coupling effects.

    PubMed

    Chung, Stephen; Vafai, Kambiz

    2014-01-03

    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. © 2013 Elsevier Ltd. All rights reserved.

  11. [PCSK9: Structure and function. PCSK9 and low-density lipoprotein receptor. Mutations and their effects].

    PubMed

    Pedro-Botet, Juan; Badimón, Lina

    2016-05-01

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein receptor (LDLr) and then targets it for lysosomal degradation in cells, thus preventing LDLr from recycling back to the hepatocyte surface, with a consequent decrease in LDLr density and clearance of LDL-cholesterol (LDLc). There have been reports of both gain-of-function mutations in the PCSK9 gene that cause a marked increase in LDLc conentrations and loss-of-function mutations, which lead to modest reductions in LDLc and low rates of coronary heart disease. The PCSK9 gene has become a promising therapeutic target to reduce blood cholesterol levels. This review discusses the most interesting recent data on PCSK9 regulation and its molecular function in cholesterol homeostasis.

  12. Antiapoptotic effects of propolis extract and propol on human macrophages exposed to minimally modified low density lipoprotein.

    PubMed

    Claus, R; Kinscherf, R; Gehrke, C; Bonaterra, G; Basnet, P; Metz, J; Deigner, H P

    2000-04-01

    An aqueous extract of propolis and the phenolic component of propolis, propol, were assayed for antioxidative and antiapoptotic properties. Both additions inhibited Cu(2+)-initiated low density lipoprotein (LDL) oxidation as characterized by a reduction of the lag time, reduced the increase of relative electrophoretic mobility during oxidation and markedly diminished apoptosis of human macrophages exposed to minimally modified (mmLDL). Moreover, aqueous propolis extract and propol blocked the mmLDL-induced decrease of glutathione (GSH) and the activation of the transcription factor NF-kappa B in these cells. The potent phenolic antioxidant propol thus expands the capability of cells to neutralize oxidative stress and to prevent apoptosis and is therefore suggested to significantly contribute to the antiinflammatory and antioxidative effects of propolis.

  13. Isradipine, a calcium-entry blocker, decreases vascular (125-I)low-density lipoprotein entry in hypercholesterolemic rabbits

    SciTech Connect

    Sinzinger, H.; Lupattelli, G.; Virgolini, I.; Gerakakis, A.; Fitscha, P.; Molinari, E.; Angelberger, P. Vienna, Austria)

    1991-04-01

    In 72 male rabbits aged 6 months, the endothelium of the abdominal aorta was abraded by a Fogarthy catheter. The animals were then fed a 1% cholesterol-supplemented diet for 4 weeks. In addition, half of the animals were treated for the entire period with isradipine (0.3 mg/kg daily), a dihydropyridine calcium antagonist; the other 36 animals served as controls. One hour and 3, 6, 12, 24, and 48 hours before the animals were killed, (125-I)low-density lipoprotein (LDL 10 microCi) was administered intravenously (i.v.) to six animals in each group. The (125-I)LDL entry was quantified in the abdominal aorta according to the type and presence of endothelial lining. Isradipine significantly reduced the (125-I)LDL entry at most time intervals. In parallel, an increase in vascular prostaglandin (PGI2) synthesis was noted, which might be the underlying mechanism for the decreased LDL entry.

  14. Lower low-density lipoprotein cholesterol levels are associated with Parkinson's disease.

    PubMed

    Huang, Xuemei; Chen, Honglei; Miller, William C; Mailman, Richard B; Woodard, Jennifer L; Chen, Peter C; Xiang, Dong; Murrow, Richard W; Wang, Yi-Zhe; Poole, Charles

    2007-02-15

    The apolipoprotein E (APOE) epsilon2 allele has been associated with both Parkinson's disease (PD) and lower low-density lipoprotein cholesterol (LDL-C). We tested the hypothesis that lower LDL-C may be associated with PD. This case-control study used fasting lipid profiles obtained from 124 PD cases and 112 controls. The PD cases were recruited from consecutive cases presenting at our tertiary Movement Disorder Clinic, and the controls were recruited from the spouse populations of the same clinic. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from unconditional logistic regressions, adjusting for age, gender, smoking status, and use of cholesterol-lowering agents. Lower LDL-C concentrations were associated with a higher occurrence of PD. Compared with participants with the highest LDL-C (> or =138 mg/dL), the OR was 2.2 (95% CI = 0.9-5.1) for participants with LDL-C of 115 to 137, 3.5 (95% CI = 1.6-8.1) for LDL-C of 93 to 114, and 2.6 (95% CI = 1.1-5.9) for LDL-C of < or = 92. Interestingly, use of either cholesterol-lowering drugs, or statins alone, was related to lower PD occurrence. Thus, our data provide preliminary evidence that low LDL-C may be associated with higher occurrence of PD, and/or that statin use may lower PD occurrence, either of which finding warrants further investigation.

  15. Very-low-density lipoprotein: complex particles in cardiac energy metabolism.

    PubMed

    Niu, You-Guo; Evans, Rhys D

    2011-01-01

    The heart is a major consumer of energy and is able to utilise a wide range of substrates including lipids. Nonesterified fatty acids (NEFA) were thought to be a favoured carbon source, but their quantitative contribution is limited because of their relative histotoxicity. Circulating triacylglycerols (TAGs) in the form of chylomicrons (CMs) and very-low-density lipoprotein (VLDL) are an alternative source of fatty acids and are now believed to be important in cardiac metabolism. However, few studies on cardiac utilisation of VLDL have been performed and the role of VLDL in cardiac energy metabolism remains unclear. Hearts utilise VLDL to generate ATP, but the oxidation rate of VLDL-TAG is relatively low under physiological conditions; however, in certain pathological states switching of energy substrates occurs and VLDL may become a major energy source for hearts. We review research regarding myocardial utilisation of VLDL and suggest possible roles of VLDL in cardiac energy metabolism: metabolic regulator and extracardiac energy storage for hearts.

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

    SciTech Connect

    Bamberger, M.J.; Lane, M.D. )

    1990-04-01

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

  17. Accumulation of 99mTc-low-density lipoprotein in human malignant glioma.

    PubMed Central

    Leppälä, J.; Kallio, M.; Nikula, T.; Nikkinen, P.; Liewendahl, K.; Jääskeläinen, J.; Savolainen, S.; Gylling, H.; Hiltunen, J.; Callaway, J.

    1995-01-01

    Low-density lipoprotein (LDL) uptake in gliomas was studied to find out if LDL has potential as a drug carrier of boron, especially for boron neutron capture therapy. Single photon emission tomography (SPET) was performed 2 h and 20 h after intravenous injection of autologous 99mTc-labelled LDL in four patients with untreated and five patients with recurrent glioma. 99mTc-LDL uptake was compared with the uptake of 99mTc-labelled human serum albumin (HSA), an established blood pool marker. The intra- and peritumoral distributions of radioactivity in the SPET images were not identical for radiolabelled LDL and HSA. The mean LDL tumour to brain ratio, determined from transversal SPET slices at 20 h post injection, was 1.5 in untreated and 2.2 in recurrent gliomas; the corresponding ratios for HSA were 1.6 and 3.4. The brain to blood ratio remained constant at 2 h and 20 h in both types of tumours. These data are not consistent with highly selective, homogeneous uptake of LDL in gliomas. However, the different tumoral distribution and rate of uptake of 99mTc-LDL, as compared with 99mTc-HSA, indicate that the uptake of LDL is different from that of HSA and that further studies on the mechanism of LDL uptake in glioma are warranted. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:7841057

  18. Whole-Cell Analysis of Low-Density Lipoprotein Uptake by Macrophages Using STEM Tomography

    PubMed Central

    Baudoin, Jean-Pierre; Jerome, W. Gray; Kübel, Christian; de Jonge, Niels

    2013-01-01

    Nanoparticles of heavy materials such as gold can be used as markers in quantitative electron microscopic studies of protein distributions in cells with nanometer spatial resolution. Studying nanoparticles within the context of cells is also relevant for nanotoxicological research. Here, we report a method to quantify the locations and the number of nanoparticles, and of clusters of nanoparticles inside whole eukaryotic cells in three dimensions using scanning transmission electron microscopy (STEM) tomography. Whole-mount fixed cellular samples were prepared, avoiding sectioning or slicing. The level of membrane staining was kept much lower than is common practice in transmission electron microscopy (TEM), such that the nanoparticles could be detected throughout the entire cellular thickness. Tilt-series were recorded with a limited tilt-range of 80° thereby preventing excessive beam broadening occurring at higher tilt angles. The 3D locations of the nanoparticles were nevertheless determined with high precision using computation. The obtained information differed from that obtained with conventional TEM tomography data since the nanoparticles were highlighted while only faint contrast was obtained on the cellular material. Similar as in fluorescence microscopy, a particular set of labels can be studied. This method was applied to study the fate of sequentially up-taken low-density lipoprotein (LDL) conjugated to gold nanoparticles in macrophages. Analysis of a 3D reconstruction revealed that newly up-taken LDL-gold was delivered to lysosomes containing previously up-taken LDL-gold thereby forming onion-like clusters. PMID:23383042

  19. Stabilization of advanced atherosclerosis in low-density lipoprotein receptor-deficient mice by aspirin.

    PubMed

    Cyrus, Tillmann; Yao, Yuemang; Tung, Liun X; Praticò, Domenico

    2006-01-01

    COX-1-dependent eicosanoid formation accelerates atherogenesis, and low-dose aspirin reduces early atherosclerosis. However, the role of aspirin in modulating progression of vascular atherosclerotic lesions once established is less investigated. We wished to determine the effect of low-dose aspirin on vascular inflammation, plaque composition, and progression of established atherosclerosis. Low-density lipoprotein receptor-deficient mice (LDLR(-/-)) were fed a high-fat diet for 3 months. At this time, one group of mice underwent baseline analysis. Two additional groups, while continuing the high-fat diet, were randomized to receive placebo or aspirin for additional 3 months. At the end of the study, LDLR(-/-) mice that had received aspirin had suppressed biosynthesis of thromboxane B2, the major products of COX-1 activity, reduced monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 levels compared with controls. Compared with baseline, the placebo group had significant progression of atherosclerosis. In contrast, aspirin treated mice showed a significant reduction in progression of atherosclerosis, and a significant decrease in foam cell content. These results suggest that in murine atherosclerosis, low-dose aspirin retards progression of established and advanced vascular atherosclerotic lesions by suppressing the formation of bioactive lipids and vascular inflammation.

  20. Inhibitory effect of oolong tea on the oxidative state of low density lipoprotein (LDL).

    PubMed

    Kurihara, Hiroshi; Fukami, Harukazu; Toyoda, Yoshiko; Kageyama, Norihiko; Tsuruoka, Nobuo; Shibata, Hiroshi; Kiso, Yoshinobu; Tanaka, Takaharu

    2003-05-01

    In the present study, we investigated the anti-oxidant activity of oolong tea in an oxidation model using human low-density lipoprotein (LDL). Oolong tea suppressed the oxidation of LDL induced by 2-2'-azobis 4-methoxy-2,4-dimethyvaleronitrile (V70) in a dose-dependent manner, that is, it prolonged the lag time to 114.3%, 138% and 199.9% as compared with the control group at 0.5 microg/ml, 1.0 microg/ml, and 2.5 microg/ml, respectively. We also determined the scavenging effect of oolong tea on active oxygen radicals using the electron spin resonance (ESR) technique with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trapping agent. The intensity of the ESR signals for the DMPO-OOH adduct formed by the hypoxanthine/xanthine oxidase reaction system with DMPO decreased in the presence of oolong tea. The IC(50) of oolong tea was 19.9 microg/ml. These findings suggested that oolong tea has beneficial effects on health related to its anti-oxidative action.

  1. Nanostructured NiO-based reagentless biosensor for total cholesterol and low density lipoprotein detection.

    PubMed

    Kaur, Gurpreet; Tomar, Monika; Gupta, Vinay

    2017-03-01

    Nanostructured nickel oxide (NiO) thin film has been explored as a matrix to develop a reagentless biosensor for free and total cholesterol as well as low density lipoprotein (LDL) detection. The redox property of the matrix has been exploited to enhance the electron transfer between the enzyme and the electrode as well as to eliminate the toxic mediator in solution. X-ray diffraction, scanning electron microscopy, atomic force microscopy, and Fourier transform infrared spectroscopy were carried out to characterize the NiO thin film. Biosensing response studies were accomplished using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and differential pulse voltammetry (DPV). The developed biosensors exhibited a high sensitivity of 27 and 63 μA/mM/cm(2) over a linear range of 0.12-10.23 and 1-12 mM, respectively, for free and total cholesterol. Reagentless estimation of LDL was also achieved over the wide range 0.018-0.5 μM with a sensitivity of 0.12 mA/μM/cm(2). The results are extremely promising for the realization of an integrated biosensor for complete detection of cholesterol in the serum samples. Graphical Abstract Reagentless sensing mechanism of (a) free cholesterol and (b) total cholesterol using nanostructured NiO matrix.

  2. Unmodified low density lipoprotein causes cholesteryl ester accumulation in J774 macrophages.

    PubMed

    Tabas, I; Weiland, D A; Tall, A R

    1985-01-01

    Cholesteryl ester (CE)-loaded macrophages (foam cells) are a prominent feature of atherosclerotic plaques. Previous studies have shown that human monocytes or resident mouse peritoneal macrophages accumulate CE in response to low density lipoprotein (LDL) only when the LDL has been appropriately chemically modified. By contrast, we report here that J774 macrophages accumulate large amounts of CE when incubated with unmodified LDL. The CE is stored in oil red O-positive droplets, which have the typical appearance of foam cell inclusions by electron microscopy. The fatty acid moieties of the cellular CE are enriched in oleate unlike those of LDL-CE, which are enriched in linoleate, indicating that the LDL-CE undergoes hydrolysis and reesterification by acyl CoA:cholesterol acyltransferase. Studies with 125I-labeled LDL at both 4 degrees C and 37 degrees C indicate that the LDL is internalized by a specific receptor that has several characteristics in common with the apolipoprotein B/E (apo B/E) receptor. However, in comparison with fibroblasts, the LDL receptor and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity in J774 cells are relatively resistant to down-regulation by LDL or 25-hydroxycholesterol, leading to receptor-mediated CE storage. In addition, J774 cells appear to accumulate CE from LDL internalized by nonspecific means. Thus, macrophage-like cells can accumulate CE in response to unmodified LDL by both nonspecific and receptor-mediated processes.

  3. Rspo2 suppresses CD36-mediated apoptosis in oxidized low density lipoprotein-induced macrophages

    PubMed Central

    Yan, Hui; Wang, Shuai; Li, Zhenwei; Sun, Zewei; Zan, Jie; Zhao, Wenting; Pan, Yanyun; Wang, Zhen; Wu, Mingjie; Zhu, Jianhua

    2016-01-01

    Oxidized low density lipoprotein (oxLDL)-induced apoptosis of macrophages contributes to the formation of atherosclerotic plaques. R-spondin 2 (Rspo2), a member of the cysteine-rich secreted proteins, has been shown to be involved in the oncogenesis of several types of cancer. It has also been found to be abundantly expressed among the four R-spondin members in macrophages. The present study was performed to determine whether Rspo2 is involved in the ox-LDL-induced apoptosis of macrophages. It was identified that Rspo2 inhibited oxLDL-induced apoptosis in the presence of endoplasmic reticulum (ER) stress activator using flow cytometry. In addition, Rspo2 was observed to suppress oxLDL-induced ER stress and reactive oxygen species production as demonstrated by western blotting. Furthermore, analysis of the role of Rspo2 in macrophage lipid uptake identified that Rspo2 negatively regulated the Dil-oxLDL uptake by inhibiting the expression of cluster of differentiation (CD)36, through the transcription factor, peroxisome proliferator-activated receptor (PPAR)-γ. The manipulation of Rspo2 had a direct effect on PPAR-γ nuclear translocation. In addition, chromatin immunoprecipitation analysis revealed that Rspo2 manipulation led to regulation of the direct binding between PPAR-γ and CD36. In conclusion, Rspo2 was found to have a negative regulatory effect during oxLDL-induced macrophage apoptosis by regulating lipid uptake. PMID:27571704

  4. Low-Density Lipoprotein Nanoparticles as Magnetic Resonance Imaging Contrast Agents1

    PubMed Central

    Corbin, Ian R; Li, Hui; Chen, Juan; Lund-Katz, Sissel; Zhou, Rong; Glickson, Jerry D; Zheng, Gang

    2006-01-01

    Abstract Low-density lipoproteins (LDLs) are a naturally occurring endogenous nanoplatform in mammalian systems. These nanoparticles (22 nm) specifically transport cholesterol to cells expressing the LDL receptor (LDLR). Several tumors overexpress LDLRs presumably to provide cholesterol to sustain a high rate of membrane synthesis. Amphiphilic gadolinium (Gd)-diethylenetria-minepentaacetic acid chelates have been incorporated into the LDL to produce a novel LDLR-targeted magnetic resonance imaging (MRI) contrast agent. The number of Gd chelates per LDL particle ranged between 150 and 496 Gd(III). In vitro studies demonstrated that Gd-labeled LDL retained a similar diameter and surface charge as the native LDL particle. In addition, Gd-labeled LDL retained selective cellular binding and uptake through LDLR-mediated endocytosis. Finally, Gd-labeled LDLs exhibited significant contrast enhancement 24 hours after administration in nude mice with human hepatoblastoma G2 xenografts. Thus, Gd-labeled LDL demonstrates potential use as a targeted MRI contrast agent for in vivo tumor detection. PMID:16820095

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

    SciTech Connect

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

    1986-04-01

    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.

  6. Lipopolysaccharide Is Cleared from the Circulation by Hepatocytes via the Low Density Lipoprotein Receptor

    PubMed Central

    Topchiy, Elena; Cirstea, Mihai; Kong, HyeJin Julia; Boyd, John H.; Wang, Yingjin; Russell, James A.; Walley, Keith R.

    2016-01-01

    Sepsis is the leading cause of death in critically ill patients. While decreased Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) function improves clinical outcomes in murine and human sepsis, the mechanisms involved have not been fully elucidated. We tested the hypothesis that lipopolysaccharide (LPS), the major Gram-negative bacteria endotoxin, is cleared from the circulation by hepatocyte Low Density Lipoprotein Receptors (LDLR)—receptors downregulated by PCSK9. We directly visualized LPS uptake and found that LPS is rapidly taken up by hepatocytes into the cell periphery. Over the course of 4 hours LPS is transported towards the cell center. We next found that clearance of injected LPS from the blood was reduced substantially in Ldlr knockout (Ldlr-/-) mice compared to wild type controls and, simultaneously, hepatic uptake of LPS was also reduced in Ldlr-/- mice. Specifically examining the role of hepatocytes, we further found that primary hepatocytes isolated from Ldlr-/- mice had greatly decreased LPS uptake. In the HepG2 immortalized human hepatocyte cell line, LDLR silencing similarly resulted in decreased LPS uptake. PCSK9 treatment reduces LDLR density on hepatocytes and, therefore, was another independent strategy to test our hypothesis. Incubation with PCSK9 reduced LPS uptake by hepatocytes. Taken together, these findings demonstrate that hepatocytes clear LPS from the circulation via the LDLR and PCSK9 regulates LPS clearance from the circulation during sepsis by downregulation of hepatic LDLR. PMID:27171436

  7. [New mutations in low-density lipoprotein receptor gene in familial hypercholesterolemia patients from Petrozavodsk].

    PubMed

    Komarova, T Yu; Golovina, A S; Grudinina, N A; Zakharova, F M; Korneva, V A; Lipovetsky, B M; Serebrenitskaya, M P; Konstantinov, V O; Vasilyev, V B; Mandelshtam, M Yu

    2013-06-01

    Using an automated fluorescent single-strand conformation polymorphism (SSCP) analysis of the entire coding region, promoter zone, and exon-intron junctions of the low-density lipoprotein (LDL) receptor gene, we examined 80 DNA samples of patients with familial hypercholesterolemia (FH) from Petrozavodsk. We revealed mutations that might cause FH in five probands, including FH-North Karelia (c.925-931del7) mutation and four previously unknown mutations. These novel mutations included a transversion (c.618T>G (p.S206R), one nucleotide insertion c.195_196insT (p.FsV66:D129X), a complex gene rearrangement c.192del10/ins8 (p.FsS65:D129X), and a single nucleotide deletion c.2191delG (p.FsV731:V736X). Three out of four novel mutations produce an open reading frame shift and the premature termination of translation. An analysis of the cDNA sequence of the LDL receptor showed that this might result in the formation of a transmembrane-domain-deficient receptor that is unable to bind and internalize the ligand. Our results suggest the absence of a strong founder effect associated with FH in the Petrozavodsk population.

  8. Low-density lipoproteins investigated under high hydrostatic pressure by elastic incoherent neutron scattering.

    PubMed

    Peters, J; Martinez, N; Lehofer, B; Prassl, R

    2017-07-01

    Human low-density lipoprotein (LDL) is a highly complex nano-particle built up of various lipid classes and a single large protein moiety (apoB-100) owning essential physiological functions in the human body. Besides its vital role as a supplier of cholesterol and fat for peripheral tissues and cells, it is also a known key player in the formation of atherosclerosis. Due to these important roles in physiology and pathology the elucidation of structural and dynamical details is of great interest. In the current study we drew a broader picture of LDL dynamics using elastic incoherent neutron scattering (EINS) as a function of specified temperature and pressure points. We not only investigated a normolipidemic LDL sample, but also a triglyceride-rich and an oxidized one to mimic pathologic conditions as found under hyperlipidemic conditions or in atherosclerotic plaques, respectively. We could show that pressure has a significant effect on atomic motions in modified forms of LDL, whereas the normolipidemic sample seems to cope much better with high-pressure conditions irrespective of temperature. These findings might be explained by the altered lipid composition, which is either caused through elevated triglyceride content or modifications through lipid peroxidation.

  9. Effects of antihypertensive therapy on platelet cytosolic calcium responses to low density lipoprotein cholesterol.

    PubMed

    Sowers, J R; Raman, B B; Afonso, L C; Bedford-Rice, K; Standley, P R

    1996-03-01

    This study examines the effects of antihypertensive therapy on platelet cytosolic calcium [Ca2+]i responses to low-density lipoprotein cholesterol (LDL) and vasopressin (AVP) in 15 patients (50-80 years) participating in the Hypertension Optimal Treatment International Study. All patients (diastolic blood pressure (DBP) > or = 100 mm Hg and < or = 115 mm Hg) were treated with the calcium antagonist felodipine (10 mg p.o.) with or without addition of enalapril (up to 20 mg daily as needed) to lower diastolic pressures to < 85 mm Hg. This antihypertensive therapy lowered DBP (104 +/- 0.8 to 78 +/- 1.6 mm Hg, P < 0.0001), but had no effect on basal [Ca2+]i or AVP-stimulated [Ca2+]i responses. Basal platelet [Ca2+]i following antihypertensive therapy (49 +/- 3.4 ng/ml) were not different from those prior to therapy (52 +/- 4.7 ng/ml). Additionally, [Ca2+]i responses to AVP following therapy (554 +/- 74 units) were not different from those prior to treatment (595 +/- 49 units). Following antihypertensive therapy, [Ca2+]i responses to 200 micrograms/ml of LDL were decreased fourfold (P < 0.05). These results suggest that antihypertensive therapy with a calcium channel blocker may potentially impact the atherogenic process by reducing the platelet [Ca2+]i rise, and potentially the aggregatory response, to LDL.

  10. Structure-based Design Targeted at LOX-1, a Receptor for Oxidized Low-Density Lipoprotein

    NASA Astrophysics Data System (ADS)

    Thakkar, Shraddha; Wang, Xianwei; Khaidakov, Magomed; Dai, Yao; Gokulan, Kuppan; Mehta, Jawahar L.; Varughese, Kottayil I.

    2015-11-01

    Atherosclerosis related cardiovascular diseases continue to be the primary cause of mortality in developed countries. The elevated level of low density lipoprotein (LDL) is generally considered to be the driver of atherosclerosis, but recent years have seen a shift in this perception in that the vascular plaque buildup is mainly caused by oxidized LDL (ox-LDL) rather than native-LDL. The scavenger receptor LOX-1 found in endothelial cells binds and internalizes ox-LDL which leads to the initiation of plaque formation in arteries. Using virtual screening techniques, we identified a few potential small molecule inhibitors of LOX-1 and tested their inhibitory potential using differential scanning fluorimetry and various cellular assays. Two of these molecules significantly reduced the uptake of ox-LDL by human endothelial cells, LOX-1 transcription and the activation of ERK1/2 and p38 MAPKs in human endothelial cells. In addition, these molecules suppressed ox-LDL-induced VCAM-1 expression and monocyte adhesion onto human endothelial cells demonstrating their therapeutic potential.

  11. The advantages of combining low-density lipoproteins with glutamine for cryopreservation of canine semen.

    PubMed

    Bencharif, D; Amirat, L; Pascal, O; Anton, M; Schmitt, E; Desherces, S; Delhomme, G; Langlois, M-L; Barrière, P; Larrat, M; Tainturier, D

    2010-04-01

    Twenty sperm samples from five dogs were frozen in liquid nitrogen at -196 degrees C in 16 different media, two control media containing 20% egg yolk and 6% low-density lipoproteins (LDL); 10 test media containing 6% LDL (the active cryoprotective ingredient of chicken egg yolk) combined with 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 mmol of glutamine respectively at 4%, 5%, 7%, and 8% LDL. Following thawing, sperm mobility was assessed using an image analyser, HAMILTON THORN CERROS 12. The percentage of mobile spermatozoa was 62.05% in the 6% LDL + 20 mmol glutamine medium compared with 48.90% in the egg yolk-based medium (p < 0.05) or 57.55% for the 6% LDL medium (p < 0.05). Furthermore, in most cases, the motility parameters (average path velocity, curvilinear velocity, straight line velocity) in the 6% LDL + 20 mmol glutamine medium, were superior, to a statistically significant extent, to those in the control media. Finally, the 6% LDL + 20 mmol glutamine combination provides spermatozoa with better protection during freezing than egg yolk or the 6% LDL medium alone in terms of acrosome integrity (fluorescein isothiocyanate--Pisum sativum agglutinin test: p < 0.05), the flagellar plasma membrane (hypo-osmotic test: p < 0.05 for 6% LDL), the DNA (acridine orange test; no significant difference) and the integrity of the acrosome (Spermac test: no significant difference).

  12. Antibodies against low-density lipoprotein receptor–related protein 4 induce myasthenia gravis

    PubMed Central

    Shen, Chengyong; Lu, Yisheng; Zhang, Bin; Figueiredo, Dwight; Bean, Jonathan; Jung, Jiung; Wu, Haitao; Barik, Arnab; Yin, Dong-Min; Xiong, Wen-Cheng; Mei, Lin

    2013-01-01

    Myasthenia gravis (MG) is the most common disorder affecting the neuromuscular junction (NMJ). MG is frequently caused by autoantibodies against acetylcholine receptor (AChR) and a kinase critical for NMJ formation, MuSK; however, a proportion of MG patients are double-negative for anti-AChR and anti-MuSK antibodies. Recent studies in these subjects have identified autoantibodies against low-density lipoprotein receptor–related protein 4 (LRP4), an agrin receptor also critical for NMJ formation. LRP4 autoantibodies have not previously been implicated in MG pathogenesis. Here we demonstrate that mice immunized with the extracellular domain of LRP4 generated anti-LRP4 antibodies and exhibited MG-associated symptoms, including muscle weakness, reduced compound muscle action potentials (CMAPs), and compromised neuromuscular transmission. Additionally, fragmented and distorted NMJs were evident at both the light microscopic and electron microscopic levels. We found that anti-LRP4 sera decreased cell surface LRP4 levels, inhibited agrin-induced MuSK activation and AChR clustering, and activated complements, revealing potential pathophysiological mechanisms. To further confirm the pathogenicity of LRP4 antibodies, we transferred IgGs purified from LRP4-immunized rabbits into naive mice and found that they exhibited MG-like symptoms, including reduced CMAP and impaired neuromuscular transmission. Together, these data demonstrate that LRP4 autoantibodies induce MG and that LRP4 contributes to NMJ maintenance in adulthood. PMID:24200689

  13. Low density lipoprotein (LDL)-antioxidant flavonoids from roots of Sophora flavescens.

    PubMed

    Jeong, Tae-Sook; Ryu, Young Bae; Kim, Hoi Young; Curtis-Long, Marcus John; An, Sojin; An, So Jin; Lee, Jin Hwan; Lee, Woo Song; Park, Ki Hun

    2008-11-01

    Oxidation of low density lipoprotein (LDL) is strongly implicated as a key process in the onset of atherosclerosis. In this study, nine alkylated (C10-C5) flavonoids from Sophora flavescens were examined for their inhibitory effects on copper-induced LDL oxidation. Of the flavonoids tested, sophoraflavanone G (1), kurarinone (2), kurarinol (3), norkurarinol (4), and kuraridin (9) inhibited the generation of thiobarbituric acid reactive substances (TBARS) with IC50s of 7.9, 14.5, 22.0, 26.9, and 17.5 microM, respectively. The most potent inhibitor, compound 1, also demonstrated significant activities in complementary in vitro investigations, such as lag time (130 min at 5 microM), relative electrophoretic mobility (REM) of ox-LDL (80% inhibition at 20 microM), and fragmentation of apoB-100 (inhibition of 71% at 20 microM). Analysis of the structures of these compounds reveals that a resorcinol moiety in the B-ring is strongly correlated with protection of LDL-oxidation.

  14. Pomegranate wine has greater protection capacity than red wine on low-density lipoprotein oxidation.

    PubMed

    Sezer, Ebru Demirel; Akçay, Yasemin Delen; Ilanbey, Bilal; Yildirim, Hatice Kalkan; Sözmen, Eser Yildirim

    2007-06-01

    Although there is a large body of evidence on the main role of red wine in protection of low-density lipoprotein (LDL) against oxidation, there are few data on the role of pomegranate juice, which has high phenolic content. We conducted this study considering the possible importance of pomegranate wine as an antioxidant and in order to make a comparison between red and pomegranate wines. The phenol levels of pomegranate and red wines (4,850 mg/L gallic acid equivalents and 815 mg/L gallic acid equivalents, respectively) were in accordance with their total antioxidant activity (39.5% and 33.7%, respectively). Both wines decreased LDL-diene levels following a 30-minute incubation period compared with controls (145 +/- 3.2 micromol/mg of LDL protein). However, pure pomegranate wine demonstrated a greater antioxidant effect (P < .01) on diene level (110 +/- 4.6 micromol/mg of LDL protein) than pure red wine (124 +/- 3.2 micromol/mg of LDL protein). In conclusion, we suggest that pomegranate wine has potential protective effects toward LDL oxidation, and it may be a dietary choice for people who prefer fruit wines.

  15. Terminalia bellirica Extract Inhibits Low-Density Lipoprotein Oxidation and Macrophage Inflammatory Response in Vitro

    PubMed Central

    Tanaka, Miori; Kishimoto, Yoshimi; Saita, Emi; Suzuki-Sugihara, Norie; Kamiya, Tomoyasu; Taguchi, Chie; Iida, Kaoruko; Kondo, Kazuo

    2016-01-01

    The deciduous tree Terminalia bellirica found in Southeast Asia is extensively used in traditional Indian Ayurvedic medicine for the treatment of hypertension, rheumatism, and diabetes. The anti-atherogenic effect of Terminalia bellirica fruit has not been fully elucidated. Here, we investigated the effect of Terminalia bellirica extract (TBE) on low-density lipoprotein (LDL) oxidation and inflammation in macrophages. TBE showed 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity (EC50: 7.2 ± 1.2 μg/mL) and 15-lipoxygenase inhibitory activity. TBE also significantly inhibited free radical-induced LDL oxidation compared to the solvent control in vitro. In THP-1 macrophages, TBE treatment resulted in significant decreases of the mRNA expression of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and lectin-like oxidized LDL receptor-1 (LOX-1). TBE also reduced matrix metalloproteinase (MMP)-9 secretion and intracellular reactive oxygen species (ROS) production in THP-1 macrophages. These results show that TBE has the inhibitory effects on LDL oxidation and macrophage inflammatory response in vitro, suggesting that its in vivo use might inhibit atherosclerosis plaque progression. PMID:27314393

  16. Phospholipase A2-modified low-density lipoprotein activates macrophage peroxisome proliferator-activated receptors.

    PubMed

    Namgaladze, Dmitry; Morbitzer, Daniel; von Knethen, Andreas; Brüne, Bernhard

    2010-02-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors modulating metabolic and inflammatory responses of phagocytes to stimuli such as fatty acids and their metabolites. We studied the role of PPARs in macrophages exposed to low-density lipoprotein (LDL) modified by secretory phospholipase A(2) (PLA). By analyzing PPAR ligand-binding domain luciferase reporter activation, we observed that PLA-LDL transactivates PPARalpha and PPARdelta, but not PPARgamma. We confirmed that PLA-LDL induced PPAR response element reporter activation by endogenous PPARalpha and PPARdelta in human THP-1 macrophages. By using THP-1 cells with a stable knockdown of PPARalpha and PPARdelta, we showed that PLA-LDL-activated PPARdelta altered macrophage gene expression related to lipid metabolism and lipid droplet formation. Although PPARalpha/delta silencing did not affect cholesterol and triglyceride accumulation in PLA-LDL-treated macrophages, PPARdelta activation by PLA-LDL attenuated macrophage inflammatory gene expression induced by interferon gamma and lipopolysaccharide. PPARdelta activation by PLA-LDL does not influence lipid accumulation in PLA-LDL-treated macrophages. However, it attenuates macrophage inflammatory responses, thus contributing to an anti-inflammatory cell phenotype.

  17. Novel fluorescently labeled peptide compounds for detection of oxidized low-density lipoprotein at high specificity.

    PubMed

    Sato, Akira; Yamanaka, Hikaru; Oe, Keitaro; Yamazaki, Yoji; Ebina, Keiichi

    2014-10-01

    The probes for specific detection of oxidized low-density lipoprotein (ox-LDL) in plasma and in atherosclerotic plaques are expected to be useful for the identification, diagnosis, prevention, and treatment for atherosclerosis. In this study, to develop a fluorescent peptide probe for specific detection of ox-LDL, we investigated the interaction of fluorescein isothiocyanate (FITC)-labeled peptides with ox-LDL using polyacrylamide gel electrophoresis. Two heptapeptides (KWYKDGD and KP6) coupled through the ε-amino group of K at the N-terminus to FITC in the presence/absence of 6-amino-n-caproic acid (AC) linker to FITC--(FITC-AC)KP6 and (FITC)KP6--both bound with high specificity to ox-LDL in a dose-dependent manner. In contrast, a tetrapeptide (YKDG) labeled with FITC at the N-terminus and a pentapeptide (YKDGK) coupled through the ε-amino group of K at the C-terminus to FITC did not bind selectively to ox-LDL. Furthermore, (FITC)KP6 and (FITC-AC)KP6 bound with high specificity to the protein in mouse plasma (probably ox-LDL fraction). These findings strongly suggest that (FITC)KP6 and (FITC-AC)KP6 may be effective novel fluorescent probes for specific detection of ox-LDL.

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

    PubMed

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

    2015-04-06

    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.

  19. Structure-based Design Targeted at LOX-1, a Receptor for Oxidized Low-Density Lipoprotein.

    PubMed

    Thakkar, Shraddha; Wang, Xianwei; Khaidakov, Magomed; Dai, Yao; Gokulan, Kuppan; Mehta, Jawahar L; Varughese, Kottayil I

    2015-11-18

    Atherosclerosis related cardiovascular diseases continue to be the primary cause of mortality in developed countries. The elevated level of low density lipoprotein (LDL) is generally considered to be the driver of atherosclerosis, but recent years have seen a shift in this perception in that the vascular plaque buildup is mainly caused by oxidized LDL (ox-LDL) rather than native-LDL. The scavenger receptor LOX-1 found in endothelial cells binds and internalizes ox-LDL which leads to the initiation of plaque formation in arteries. Using virtual screening techniques, we identified a few potential small molecule inhibitors of LOX-1 and tested their inhibitory potential using differential scanning fluorimetry and various cellular assays. Two of these molecules significantly reduced the uptake of ox-LDL by human endothelial cells, LOX-1 transcription and the activation of ERK1/2 and p38 MAPKs in human endothelial cells. In addition, these molecules suppressed ox-LDL-induced VCAM-1 expression and monocyte adhesion onto human endothelial cells demonstrating their therapeutic potential.

  20. Rutaecarpine Reverses the Altered Connexin Expression Pattern Induced by Oxidized Low-density Lipoprotein in Monocytes.

    PubMed

    Liu, Yong; Fu, Yan-Qi; Peng, Wei-Jie; Yu, Yan-Rong; Wu, Yu-Si; Yan, Hang; Huang, Qi-Ren; He, Ming; Luo, Dan

    2016-06-01

    Adhesion of monocytes to the vascular endothelium is crucial in atherosclerosis development. Connexins (Cxs) which form hemichannels or gap junctions, modulate monocyte-endothelium interaction. We previously found that rutaecarpine, an active ingredient of the Chinese herbal medicine Evodia, reversed the altered Cx expression induced by oxidized low-density lipoprotein (ox-LDL) in human umbilical vein endothelial cells, and consequently decreases the adhesive properties of endothelial cells to monocytes. This study further investigated the effect of rutaecarpine on Cx expression in monocytes exposed to ox-LDL. In cultured human monocytic cell line THP-1, ox-LDL rapidly reduced the level of atheroprotective Cx37 but enhanced that of atherogenic Cx43, thereby inhibiting adenosine triphosphate release through hemichannels. Pretreatment with rutaecarpine recovered the expression of Cx37 but inhibited the upregulation of Cx43 induced by ox-LDL, thereby improving adenosine triphosphate-dependent hemichannel activity and preventing monocyte adhesion. These effects of rutaecarpine were attenuated by capsazepine, an antagonist of transient receptor potential vanilloid subtype 1. The antiadhesive effects of rutaecarpine were also attenuated by hemichannel blocker 18α-GA. This study provides additional evidence that rutaecarpine can modulate Cx expression through transient receptor potential vanilloid subtype 1 activation in monocytes, which contributes to the antiadhesive properties of rutaecarpine.

  1. Purification and Characterization of a Bovine Acetyl Low Density Lipoprotein Receptor

    NASA Astrophysics Data System (ADS)

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

    1988-12-01

    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.

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

    PubMed Central

    Gursky, Olga

    2014-01-01

    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

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

    NASA Astrophysics Data System (ADS)

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

    2014-06-01

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

  4. Angiotensin II induces the aggregation of native and oxidized low-density lipoprotein.

    PubMed

    Sato, Akira; Ueda, Chiemi; Kimura, Ryu; Kobayashi, Chisato; Yamazaki, Yoji; Ebina, Keiichi

    2017-04-11

    Modifications of low-density lipoprotein (LDL), such as oxidation and aggregation, and angiotensin (Ang) peptides are involved in the pathogenesis of atherosclerosis. Here, we investigated the relationship between one of the Ang peptides, AngII, and two LDL modifications, oxidation and aggregation. Using polyacrylamide gel electrophoresis and aggregation assays, we noted that AngII markedly induced the aggregation of LDL and oxidized LDL (Ox-LDL), and bound to both the aggregated and non-aggregated forms. In contrast, a peptide (AngIII) formed by deletion of N-terminal Asp of AngII induced the aggregation of Ox-LDL but not LDL. From tyrosine fluorescence measurements, we noted that AngII interacted with two major lipid components in LDL and Ox-LDL, phosphatidylcholine (PC) and oxidized PC, while AngIII interacted with oxidized PC, but not with PC and lysophosphatidylcholine. Moreover, results from thiobarbituric acid-reactive substances assay proved that AngII did not induce oxidation of LDL. These results suggest that AngII can be involved in the pathogenesis of atherosclerosis by binding to LDL and Ox-LDL-especially to the major lipid components, PC and oxidized PC-followed by inducing the aggregation of LDL and Ox-LDL and that the N-terminal Asp of AngII is important for the binding and aggregation specificity of LDL and Ox-LDL.

  5. Role of low density lipoprotein-bound cholesterol esters in acute lymphoblastic leukemia cells

    SciTech Connect

    Cutts, J.L.; Madden, E.A.; Melnykovych, G.

    1986-05-01

    The glucocorticoid sensitive CEM-C7 T-cell line was derived from human acute lymphoblastic leukemia cells by Norman and Thompson. Madden et al. have demonstrated that this growth inhibitory effect is due in part to a glucocorticoid-mediated inhibition of cholesterol synthesis and can be partially reversed by cholesterol dispersions. To further delineate the role of cholesterol in this growth inhibition, they have examined the ability of low density lipoprotein (LDL)-bound (/sup 3/H)cholesterol linoleate to reverse the growth inhibitory effect of 1 ..mu..M dexamethasone (Dex) on the CEM-C7 cells. LDL-bound cholesterol linoleate was unable to reverse the Dex-mediated growth inhibition, although incorporation of (/sup 14/C) acetate into free cholesterol was inhibited by 29%, following the Brown and Goldstein model. The presence of Dex further inhibited acetate incorporation into free cholesterol in the LDL-treated cells. Under all conditions, more than 99% of the acetate incorporated into cholesterol was present as free cholesterol, while over 87% of the LDL-bound cholesterol linoleate taken up remained in the ester compartment. These results indicate that CEM-C7 cells are unable to utilize LDL-bound cholesterol esters as a source of free cholesterol and rely on endogenous synthesis for their free cholesterol requirements.

  6. Targeting low-density lipoprotein receptors with protein-only nanoparticles

    NASA Astrophysics Data System (ADS)

    Xu, Zhikun; Céspedes, María Virtudes; Unzueta, Ugutz; Álamo, Patricia; Pesarrodona, Mireia; Mangues, Ramón; Vázquez, Esther; Villaverde, Antonio; Ferrer-Miralles, Neus

    2015-03-01

    Low-density lipoprotein receptors (LDLR) are appealing cell surface targets in drug delivery, as they are expressed in the blood-brain barrier (BBB) endothelium and are able to mediate transcytosis of functionalized drugs for molecular therapies of the central nervous system (CNS). On the other hand, brain-targeted drug delivery is currently limited, among others, by the poor availability of biocompatible vehicles, as most of the nanoparticles under development as drug carriers pose severe toxicity issues. In this context, protein nanoparticles offer functional versatility, easy and cost-effective bioproduction, and full biocompatibility. In this study, we have designed and characterized several chimerical proteins containing different LDLR ligands, regarding their ability to bind and internalize target cells and to self-organize as viral mimetic nanoparticles of about 18 nm in diameter. While the self-assembling of LDLR-binding proteins as nanoparticles positively influences cell penetration in vitro, the nanoparticulate architecture might be not favoring BBB crossing in vivo. These findings are discussed in the context of the use of nanostructured materials as vehicles for the systemic treatment of CNS diseases.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  8. Accumulation of oxidized low-density lipoprotein in psoriatic skin and changes of plasma lipid levels in psoriatic patients.

    PubMed

    Tekin, Nilgun Solak; Tekin, Ishak Ozel; Barut, Figen; Sipahi, Emine Yilmaz

    2007-01-01

    Psoriasis is a chronic inflammatory skin disease characterized by an accelerated turnover of epidermal cells and an incomplete differentiation in epidermis with lesion. However, the exact etiology of psoriasis is unknown. Abnormalities in essential fatty acid metabolism, free radical generation, lipid peroxidation, and release of lymphokines have been proposed. Our purpose was to evaluate the plasma lipids and oxidized low-density lipoprotein accumulation in psoriatic skin lesion in order to ascertain the possible participation of oxidative stress and oxidative modification of lipids in pathogenesis of psoriasis. The study group included 84 patients with psoriasis, and 40 sex- and age-matched healthy volunteers. Blood lipid profile was determined. Psoriatic and nonlesional skin samples of psoriatic patients were evaluated for the presence of oxidized low-density lipoprotein by using an immune-fluorescent staining method. The mean levels of lipids (total cholesterol, triglyceride, and LDL cholesterol) in patients with psoriasis were found to be significantly higher than those of healthy subjects. Psoriatic skins were shown positive oxidized low-density lipoprotein staining. There was no staining in nonlesional skin samples of the same individuals. Lipid peroxidation mediated by free radicals is believed to be one of the important causes of cell membrane destruction and cell damage. This study shows for the first time the accumulation of oxidized low-density lipoprotein in psoriatic skin lesion. We believe that accumulation of ox-LDL in psoriatic skin may have an important role in the immune-inflammatory events that result in progressive skin damage.

  9. Comparative time-courses of copper-ion-mediated protein and lipid oxidation in low-density lipoprotein.

    PubMed

    Knott, Heather M; Baoutina, Anna; Davies, Michael J; Dean, Roger T

    2002-04-15

    Free radicals damage both lipids and proteins and evidence has accumulated for the presence of both oxidised lipids and proteins in aged tissue samples as well as those from a variety of pathologies including atherosclerosis, diabetes, and Parkinson's disease. Oxidation of the protein and lipid moieties of low-density lipoprotein is of particular interest due to its potential role in the unregulated uptake of lipids and cholesterol by macrophages; this may contribute to the initial stage of foam cell formation in atherosclerosis. In the study reported here, we examined the comparative time-courses of lipid and protein oxidation during copper-ion-mediated oxidation of low-density lipoprotein. We show that there is an early, lipid-mediated loss of 40-50% of the Trp residues of the apoB100 protein. There is no comparable loss over an identical period during the copper-ion-mediated oxidation of lipid-free BSA. Concomitant with Trp loss, the antioxidant alpha-tocopherol is consumed with subsequent extensive lipid peroxidation. Further changes to the protein, including the copper-ion-dependent 3.5-fold increase in 3,4-dihydroxyphenylalanine and the copper-ion-independent 3-5-fold increase in o-tyrosine, oxidation products of Tyr and Phe, respectively, only occur after maximal lipid peroxidation. Long incubation periods result in depletion of 3,4-dihydroxyphenylalanine, presumably reflecting further oxidative changes. Overall, copper-ion-mediated oxidation of LDL appears to proceed initially by lipid radical-dependent processes, even though some of the earliest detectable changes occur on the apoB100 protein. This is followed by extensive lipid peroxidation and subsequent additional oxidation of aromatic residues on apoB100, though it is not yet clear whether this late protein oxidation is lipid-dependent or occurs as a result of direct radical attack.

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

    NASA Technical Reports Server (NTRS)

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

    1999-01-01

    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.

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

    NASA Technical Reports Server (NTRS)

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

    1999-01-01

    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.

  12. Oxidized Low-Density Lipoprotein Contributes to Atherogenesis via Co-activation of Macrophages and Mast Cells

    PubMed Central

    Chen, Chong; Khismatullin, Damir B.

    2015-01-01

    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)-α, 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-α and histamine in the supernatants were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. A low dose of oxLDL (8 μg/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-α and histamine. The direct exposure of endothelial cells to a much higher dose of oxLDL (80 μg/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

  13. Oxidized low-density lipoprotein contributes to atherogenesis via co-activation of macrophages and mast cells.

    PubMed

    Chen, Chong; Khismatullin, Damir B

    2015-01-01

    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)-α, 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-α and histamine in the supernatants were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. A low dose of oxLDL (8 μg/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-α and histamine. The direct exposure of endothelial cells to a much higher dose of oxLDL (80 μg/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.

  14. Role of endogenous ceruloplasmin in low density lipoprotein oxidation by human U937 monocytic cells.

    PubMed Central

    Ehrenwald, E; Fox, P L

    1996-01-01

    Oxidation of lipids and lipoproteins by macrophages is an important event during atherogenesis. Activation of monocytic cells by zymosan and other agonists results in the release of multiple oxidant species and consequent oxidation of LDL. We now show evidence that ceruloplasmin, a copper-containing acute phase reactant, is secreted by zymosan-activated U937 monocytic cells, and that the protein has an important role in LDL oxidation by these cells. In one approach, ceruloplasmin has been shown to exhibit oxidant activity under the appropriate conditions. Exogenous addition of purified human ceruloplasmin stimulates U937 cell oxidation of LDL to nearly the same extent as activation by zymosan. In contrast to previous cell-free experiments (Ehrenwald, E., G.M. Chisom, and P.L. Fox. 1994. Intact human ceruloplasmin oxidatively modifies low density lipoprotein. J. Clin. Invest. 93:1493-1501.) in which ceruloplasmin by itself (in PBS) oxidizes LDL, under the conditions of the current experiments (in RPMI 1640 medium) ceruloplasmin only oxidizes LDL in the presence of cells; the mechanism by which cells overcome the inhibition by medium components has not been ascertained. As further evidence for a role of ceruloplasmin, activation of U937 cells with zymosan induces ceruloplasmin mRNA and ceruloplasmin protein synthesis after a 5-6 h lag that is consistent with that preceding LDL oxidation. Finally, neutralization by a highly specific polyclonal antibody to human ceruloplasmin inhibits LDL oxidation by at least 65%. Moreover, multiple antisense oligodeoxynucleotides targeted to different regions of the ceruloplasmin mRNA block LDL oxidation by up to 95%. The specific action of the antisense oligonucleotides has been verified by showing inhibition of ceruloplasmin synthesis and by the ability of exogenous ceruloplasmin to overcome the inhibition. In summary, these results are consistent with a mechanism in which cell-derived ceruloplasmin participates in oxidation of LDL

  15. Oxidized low-density lipoprotein as a biomarker of cardiovascular diseases.

    PubMed

    Trpkovic, Andreja; Resanovic, Ivana; Stanimirovic, Julijana; Radak, Djordje; Mousa, Shaker A; Cenic-Milosevic, Desanka; Jevremovic, Danimir; Isenovic, Esma R

    2015-01-01

    Atherosclerosis is a life-long illness that begins with risk factors, which in turn contribute to the development of subclinical disease, followed by the establishment of overt cardiovascular disease (CVD). Thrombotic-occlusive complications of atherosclerosis are among the most widespread and costly health problems. Oxidized low-density lipoprotein (OxLDL) plays an important role in atherogenesis by promoting an inflammatory environment and lipid deposition in the arterial wall. As cardiovascular events occur in individuals without common risk factors, there is a need for additional tools that may help in CVD risk assessment and management. The use of biomarkers has improved diagnostic, therapeutic and prognostic outcome in cardiovascular medicine. This review elaborates on the value of circulating OxLDL as a biomarker of CVD. Three enzyme-linked immunosorbent assays (4E6, DLH3 and E06) using murine monoclonal antibodies for determination of OxLDL blood levels have been developed. However, none of these assays are currently approved for routine clinical practice. We identified studies investigating OxLDL in CVD (measured by 4E6, DLH3 or E06 assay) by searching the PubMed database. Circulating OxLDL was found to be associated with all stages of atherosclerosis, from early atherogenesis to hypertension, coronary and peripheral arterial disease, acute coronary syndromes and ischemic cerebral infarction. The results of studies investigating the usefulness of OxLDL for CVD prediction were also summarized. Furthermore, OxLDL was found to be associated with pathologic conditions linked to CVD, including diabetes mellitus, obesity and metabolic syndrome (MetS). In addition, we have addressed the mechanisms by which OxLDL promotes atherogenesis, and the effects of antiatherogenic treatments on circulating OxLDL. Finally, we highlight the evidence suggesting that lipoprotein (a) [Lp(a)] is the preferential carrier of oxidized phospholipids (OxPL) in human plasma. A strong

  16. Steatohepatitis and liver fibrosis are predicted by the characteristics of very low density lipoprotein in nonalcoholic fatty liver disease

    PubMed Central

    Jiang, Zhenghui G.; Tapper, Elliot B.; Connelly, Margery A.; Pimentel, Carolina F. M. G.; Feldbrügge, Linda; Kim, Misung; Krawczyk, Sarah; Afdhal, Nezam; Robson, Simon C.; Herman, Mark A.; Otvos, James D.; Mukamal, Kenneth J.; Lai, Michelle

    2016-01-01

    Background & Aims A major challenge in the management of nonalcoholic fatty liver disease (NAFLD) is to identify patients with nonalcoholic steatohepatitis (NASH) and early liver fibrosis. The progression of NAFLD is accompanied by distinctive changes in very low density lipoprotein (VLDL), a lipoprotein particle produced exclusively in the liver. Herein, we sought to determine the characteristics of VLDL profiles associated with NASH and liver fibrosis. Methods We evaluated VLDL profiles of 128 patients from a single centre NAFLD registry, and examined VLDL size, total and subclass VLDL concentrations in relation to NAFLD activity score (NAS), steatohepatitis and liver fibrosis as determined by liver biopsy. Results A near linear relationship was observed between mean VLDL particle size and NAFLD activity score (NAS). In multivariate models, VLDL particle size was significantly associated with both NAS and NASH, after adjustment for BMI and diabetes. A decrease in small VLDL particle concentration was associated with more advanced liver fibrosis. In receiver operative characteristic analyses, mean VLDL size performed similarly to cytokeratin 18 in predicting NASH, whereas small VLDL particle concentration had similar performance to NAFLD fibrosis score in predicting stage 2 or above liver fibrosis. Conclusions The increase in mean VLDL size in NASH and decrease in small VLDL particle concentration in liver fibrosis likely reflect changes in the number and state of hepatocytes associated with NASH and fibrosis. In addition to its value in risk stratification of cardiovascular diseases, circulating VLDL profile may provide information for the staging of NAFLD disease severity. PMID:26815314

  17. Are oxidized low-density lipoprotein and C-reactive protein markers of atherosclerosis in nephrotic children?

    PubMed

    Rybi-Szumińska, A; Wasilewska, A; Michaluk-Skutnik, J; Osipiuk-Remża, B; Fiłonowicz, R; Zając, M

    2015-12-01

    Lipid disorders are known to be linked to disturbance in oxidative reactions and play an important role in the progression and complications of idiopathic nephrotic syndrome (INS). The aim of this study was to assess oxidized low-density lipoprotein (oxLDL), high-sensitive C-reactive protein (hs-CRP) serum concentrations and other parameters of lipid metabolism in children with INS during relapse and remission of proteinuria. The examination was performed on 23 children and adolescents diagnosed with INS. Reference group consisted of 22 participants. The study was carried out twice: in the relapse of INS (A) and in remission of proteinuria during glucocorticoid treatment (B). OxLDL was higher in INS patients, in both examinations when compared with reference participants. hs-CRP showed no differences between nephrotic and healthy children. We found higher concentration of oxLDL in children, who where frequent relapsers. Cholesterol, triglycerides/high density lipoprotein cholesterol and platelets were higher in INS patients (both A and B) in comparison with healthy children. We observed presence of pro-atherogenic lipid profile in INS. Elevation of oxLDL may reflect increased oxidative stress and higher risk of atherosclerosis in INS, therefore it seems to be relevant to find patients of risk of atherosclerosis to consider lipid lowering treatment with antioxidants.

  18. Low Density Lipoprotein and Non-Newtonian Oscillating Flow Biomechanical Parameters for Normal Human Aorta

    PubMed Central

    Soulis, Johannes V.; Fytanidis, Dimitrios K.; Lampri, Olga P.; Giannoglou, George D.

    2016-01-01

    Background The temporal variation of the hemodynamic mechanical parameters during cardiac pulse wave is considered as an important atherogenic factor. Applying non-Newtonian blood molecular viscosity simulation is crucial for hemodynamic analysis. Understanding low density lipoprotein (LDL) distribution in relation to flow parameters will possibly spot the prone to atherosclerosis aorta regions. Methods The biomechanical parameters tested were averaged wall shear stress (AWSS), oscillatory shear index (OSI) and relative residence time (RRT) in relation to the LDL concentration. Four non-Newtonian molecular viscosity models and the Newtonian one were tested for the normal human aorta under oscillating flow. The analysis was performed via computational fluid dynamic. Results Tested viscosity blood flow models for the biomechanical parameters yield a consistent aorta pattern. High OSI and low AWSS develop at the concave aorta regions. This is most noticeable in downstream flow region of the left subclavian artery and at concave ascending aorta. Concave aorta regions exhibit high RRT and elevated LDL. For the concave aorta site, the peak LDL value is 35.0% higher than its entrance value. For the convex site, it is 18.0%. High LDL endothelium regions located at the aorta concave site are well predicted with high RRT. Conclusions We are in favor of using the non-Newtonian power law model for analysis. It satisfactorily approximates the molecular viscosity, WSS, OSI, RRT and LDL distribution. Concave regions are mostly prone to atherosclerosis. The flow biomechanical factor RRT is a relatively useful tool for identifying the localization of the atheromatic plaques of the normal human aorta. PMID:28197271

  19. Characterization of the structure of polydisperse human low-density lipoprotein by neutron scattering.

    PubMed

    Meyer, D F; Nealis, A S; Bruckdorfer, K R; Perkins, S J

    1995-09-01

    Low-density lipoproteins (LDL) in plasma are constructed from a single molecule of apolipoprotein B-100 (M(r) 512000) in association with lipid (approximate M(r) 2-3 x 10(6)). The gross structure was studied using an updated pulsed-neutron camera LOQ with an area detector to establish the basis for the interpretation of structural changes seen during dynamic studies of LDL oxidation. Neutron-scattering data for LDL in 100% 2H2O buffers emphasize their external appearance. Guinier analysis on a continuous-flux neutron camera D17 revealed pronounced concentration-dependences in the radius of gyration, RG, and the intensity of forward scattering, I(0) (equivalent to the M(r) of LDL) between 0.5 and 11 mg of LDL protein/ml. LDL preparations from different donors gave different RG values. When extrapolated to zero concentration, RG values ranged between 8.3 and 10.6 nm and were linearly correlated with M(r), which is consistent with a spherical structure. The distance-distribution function P(r) in real space showed a single maximum at 9.1-10.9 nm, which is just under half the observed maximum dimension of 23.1 +/- 1.2 nm expected for a spherical structure. The neutron radial-density function p(r) exhibited a plateau of high and featureless density at the centre of LDL. LDL can be modelled by a polydisperse assembly of spheres with two internal densities and a mean radius close to 10.0 nm in a normal distribution of radii with a standard deviation of 2.0 nm. The data are consistent with recent electron-microscopy and ultracentrifugation data.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Low-density lipoprotein cholesterol lowering in the prevention of CHD: how low should we go?

    PubMed

    Isley, William L

    2006-08-01

    The past 12 years have seen the publication of numerous randomized placebo-controlled studies using statins to lower low-density lipoprotein cholesterol (LDLC) to assess the efficacy of cholesterol lowering on cardiovascular events. Initial studies predominantly evaluated mortality or nonfatal myocardial infarctions and coronary heart disease (CHD) death in patients with known or presumed established coronary disease and moderately elevated to very elevated serum cholesterol concentrations. Subsequent investigations studied a broader spectrum of cardiovascular events as a composite primary end point in both primary and secondary prevention strategies in subjects with lower mean entry serum LDLC concentrations. These studies have generally shown a reduction in a composite end point of cardiovascular events, although not necessarily the more restricted end points used in previous studies. Although the LDLC mantra "lower is better" has been popularized in advertising and continuing medical education and suggested as an option in "very high risk" patients by the National Cholesterol Education Program Adult Treatment Panel, the precise target level for LDLC for optimal treatment has not been rigorously defined. Serum LDLC less than 100 mg/dL seems reasonable for patients with known atherosclerosis or at high risk for atherosclerosis (diabetes or presence of multiple risk factors). Serum LDLC less than 70 mg/dL may be a reasonable goal in the setting of acute coronary syndromes, but there are many problems with the data on which this recommendation is made. Furthermore, many advocates of "lower is better" seem oblivious to the potential downsides of more aggressive lipid-lowering therapy. The LDLC target in lower risk primary prevention is less clear. What is obvious is that moderate-dose statin therapy can lower CHD risk in primary prevention and secondary prevention with minimal side effects, and with the imminent availability of several generic statins, with great

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

    SciTech Connect

    Isaacsohn, J.L.; Lees, A.M.; Lees, R.S.; Kovach, M.B.; Strauss, H.W.

    1984-01-01

    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.

  2. Core lipid structure is a major determinant of the oxidative resistance of low density lipoprotein.

    PubMed Central

    Schuster, B; Prassl, R; Nigon, F; Chapman, M J; Laggner, P

    1995-01-01

    The influence of thermally induced changes in the lipid core structure on the oxidative resistance of discrete, homogeneous low density lipoprotein (LDL) subspecies (d, 1.0297-1.0327 and 1.0327-1.0358 g/ml) has been evaluated. The thermotropic transition of the LDL lipid core at temperatures between 15 degrees C and 37 degrees C, determined by differential scanning calorimetry, exerted significant effects on the kinetics of copper-mediated LDL oxidation expressed in terms of intrinsic antioxidant efficiency (lag time) and diene production rate. Thus, the temperature coefficients of oxidative resistance and maximum oxidation rate showed break points at the core transition temperature. Temperature-induced changes in copper binding were excluded as the molecular basis of such effects, as the saturation of LDL with copper was identical below and above the core transition. At temperatures below the transition, the elevation in lag time indicated a greater resistance to oxidation, reflecting a higher degree of antioxidant protection. This effect can be explained by higher motional constraints and local antioxidant concentrations, the latter resulting from the freezing out of antioxidants from crystalline domains of cholesteryl esters and triglycerides. Below the transition temperature, the conjugated diene production rate was decreased, a finding that correlated positively with the average size of the cooperative units of neutral lipids estimated from the calorimetric transition width. The reduced accessibility and structural hindrance in the cluster organization of the core lipids therefore inhibits peroxidation. Our findings provide evidence for a distinct effect of the dynamic state of the core lipids on the oxidative susceptibility of LDL and are therefore relevant to the atherogenicity of these cholesterol-rich particles. PMID:7708675

  3. Low-Density-Lipoprotein Particle Size Predicts a Poor Outcome in Patients with Atherothrombotic Stroke

    PubMed Central

    Song, Tae-Jin; Cho, Hyun-Ji; Chang, Yoonkyung; Youn, Minjung; Shin, Min-Jeong; Jo, Inho; Heo, Ji Hoe

    2015-01-01

    Background and Purpose Low-density lipoprotein (LDL) particle size is considered to be one of the more important cardiovascular risk factors, and small LDL particles are known to have atherogenic potential. The aim of this study was to determine whether LDL particle size is associated with stroke severity and functional outcome in patients with atherothrombotic stroke. Methods Between January 2009 and May 2011, 248 patients with first-episode cerebral infarction who were admitted to our hospital within 7 days after symptom onset were prospectively enrolled. LDL particle size was measured using the nondenaturing polyacrylamide gradient gel electrophoresis assay. Stroke severity was assessed by applying the National Institutes of Health Stroke Scale (NIHSS) at admission. Functional outcome was investigated at 3 months after the index stroke using the modified Rankin Scale (mRS), and poor functional outcome was defined as an mRS score of ≥3. Results The LDL particle size in the 248 patients was 25.9±0.9 nm (mean±SD). LDL particle size was inversely correlated with the degree of cerebral artery stenosis (p=0.010). Multinomial multivariate logistic analysis revealed that after adjustment for age, sex, and variables with p<0.1 in univariate analysis, LDL particle size was independently and inversely associated with stroke severity (NIHSS score ≥5; reference, NIHSS score 0-2; odds ratio=0.38, p=0.028) and poor functional outcome (odds ratio=0.44, p=0.038). Conclusions The results of this study demonstrate that small LDL particles are independently correlated with stroke outcomes. LDL particle size is thus a potential biomarker for the prognosis of atherothrombotic stroke. PMID:25628741

  4. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding.

    PubMed Central

    Innerarity, T L; Weisgraber, K H; Arnold, K S; Mahley, R W; Krauss, R M; Vega, G L; Grundy, S M

    1987-01-01

    Previous in vivo turnover studies suggested that retarded clearance of low density lipoproteins (LDL) from the plasma of some hypercholesterolemic patients is due to LDL with defective receptor binding. The present study examined this postulate directly by receptor binding experiments. The LDL from a hypercholesterolemic patient (G.R.) displayed a reduced ability to bind to the LDL receptors on normal human fibroblasts. The G.R. LDL possessed 32% of normal receptor binding activity (approximately equal to 9.3 micrograms of G.R. LDL per ml were required to displace 50% of 125I-labeled normal LDL, vs. approximately equal to 3.0 micrograms of normal LDL per ml). Likewise, the G.R. LDL were much less effective than normal LDL in competing with 125I-labeled normal LDL for cellular uptake and degradation and in stimulating intracellular cholesteryl ester synthesis. The defect in LDL binding appears to be due to a genetic abnormality of apolipoprotein B-100: two brothers of the proband possess LDL defective in receptor binding, whereas a third brother and the proband's son have normally binding LDL. Further, the defect in receptor binding does not appear to be associated with an abnormal lipid composition or structure of the LDL: the chemical and physical properties of the particles were normal, and partial delipidation of the LDL did not alter receptor binding activity. Normal and abnormal LDL subpopulations were partially separated from plasma of two subjects by density-gradient ultracentrifugation, a finding consistent with the presence of a normal and a mutant allele. The affected family members appear to be heterozygous for this disorder, which has been designated familial defective apolipoprotein B-100. These studies indicate that the defective receptor binding results in inefficient clearance of LDL and the hypercholesterolemia observed in these patients. PMID:3477815

  5. Cholesteryl Ester Hydroperoxides Are Biologically Active Components of Minimally Oxidized Low Density Lipoprotein*S⃞

    PubMed Central

    Harkewicz, Richard; Hartvigsen, Karsten; Almazan, Felicidad; Dennis, Edward A.; Witztum, Joseph L.; Miller, Yury I.

    2008-01-01

    Oxidation of low density lipoprotein (LDL) occurs in vivo and significantly contributes to the development of atherosclerosis. An important mechanism of LDL oxidation in vivo is its modification with 12/15-lipoxygenase (LO). We have developed a model of minimally oxidized LDL (mmLDL) in which native LDL is modified by cells expressing 12/15LO. This mmLDL activates macrophages inducing membrane ruffling and cell spreading, activation of ERK1/2 and Akt signaling, and secretion of proinflammatory cytokines. In this study, we found that many of the biological activities of mmLDL were associated with cholesteryl ester (CE) hydroperoxides and were diminished by ebselen, a reducing agent. Liquid chromatography coupled with mass spectroscopy demonstrated the presence of many mono- and polyoxygenated CE species in mmLDL but not in native LDL. Nonpolar lipid extracts of mmLDL activated macrophages, although to a lesser degree than intact mmLDL. The macrophage responses were also induced by LDL directly modified with immobilized 12/15LO, and the nonpolar lipids extracted from 12/15LO-modified LDL contained a similar set of oxidized CE. Cholesteryl arachidonate modified with 12/15LO also activated macrophages and contained a similar collection of oxidized CE molecules. Remarkably, many of these oxidized CE were found in the extracts of atherosclerotic lesions isolated from hyperlipidemic apoE–/– mice. These results suggest that CE hydroperoxides constitute a class of biologically active components of mmLDL that may be relevant to proinflammatory activation of macrophages in atherosclerotic lesions. PMID:18263582

  6. Protection of low density lipoprotein oxidation at chemical and cellular level by the antioxidant drug dipyridamole.

    PubMed Central

    Iuliano, L.; Colavita, A. R.; Camastra, C.; Bello, V.; Quintarelli, C.; Alessandroni, M.; Piovella, F.; Violi, F.

    1996-01-01

    1. The oxidative modification of low density lipoprotein (LDL) is thought to be an important factor in the initiation and development of atherosclerosis. Natural and synthetic antioxidants have been shown to protect LDL from oxidation and to inhibit atherosclerosis development in animals. Synthetic antioxidants are currently being tested, by they are not necessarily safe for human use. 2. We have previously reported that dipyridamole, currently used in clinical practice, is a potent scavenger of free radicals. Thus, we tested whether dipyridamole could affect LDL oxidation at chemical and cellular level. 3. Chemically induced LDL oxidation was made by Cu(II), Cu(II) plus hydrogen peroxide or peroxyl radicals generated by thermolysis of 2,2'-azo-bis(2-amidino propane). Dipyridamole, (1-10 microM), inhibited LDL oxidation as monitored by diene formation, evolution of hydroperoxides and thiobarbituric acid reactive substances, apoprotein modification and by the fluorescence of cis-parinaric acid. 4. The physiological relevance of the antioxidant activity was validated by experiments at the cellular level where dipyridamole inhibited endothelial cell-mediated LDL oxidation, their degradation by monocytes, and cytotoxicity. 5. In comparison with ascorbic acid, alpha-tocopherol and probucol, dipyridamole was the more efficient antioxidant with the following order of activity: dipyridamole > probucol > ascorbic acid > alpha-tocopherol. The present study shows that dipyridamole inhibits oxidation of LDL at pharmacologically relevant concentrations. The inhibition of LDL oxidation is unequivocally confirmed by use of three different methods of chemical oxidation, by several methods of oxidation monitoring, and the pharmacological relevance is demonstrated by the superiority of dipyridamole over the naturally occurring antioxidants, ascorbic acid and alpha-tocopherol and the synthetic antioxidant probucol. Images Figure 6 PMID:8968553

  7. The association between oxidized low-density lipoprotein antibodies and hematological diseases.

    PubMed

    Li, Hao; Li, Da-Qing; Li, Xiang-Xin; Wang, Lu-Qun

    2016-11-08

    The aim of the study is to compare the profiles of antibodies (IgM and IgG) against oxidized low-density lipoprotein (oxLDL) of hematological diseases. The serum antibodies of oxLDL-IgM and oxLDL-IgG for 446 cases with hematological diseases and 90 patients with primary hypertension and 90 healthy controls were measured by enzyme-linked immunosorbent assay (ELISA) in a cross-section survey. The association of serum oxLDL-LgM and oxLDL-IgG with hematological diseases was analyzed by multiple linear regression model. Comparing with the hypertension or normal groups, the levels of TCH, TG, LDL-c, HDL-c, oxLDL, and oxLDL-IgG were lower and the levels of ADP and oxLDL-IgM were higher in the hematological diseases group. The levels of oxLDL-IgG antibodies titer were different among hematological diseases group. The results of correlation and multiple regression analysis showed that the seven hematological disease subgroups were positively related to the oxLDL-IgM antibody titer but negatively related to the oxLDL-IgG antibody titer, having been adjusted for potential confounding factors such as age, SBP, DBP, BMI, TCH, TG, ADP, oxLDL, HDL-c, LDL-C. Here we show that oxLDL-IgG antibodies titer were lower and of oxLDL-IgM titer were higher than hypertension and healthy individuals. Also oxLDL-IgG titer were different among hematological diseases group.

  8. Low-density-lipoprotein particle size predicts a poor outcome in patients with atherothrombotic stroke.

    PubMed

    Song, Tae-Jin; Cho, Hyun-Ji; Chang, Yoonkyung; Youn, Minjung; Shin, Min-Jeong; Jo, Inho; Heo, Ji Hoe; Kim, Yong-Jae

    2015-01-01

    Low-density lipoprotein (LDL) particle size is considered to be one of the more important cardiovascular risk factors, and small LDL particles are known to have atherogenic potential. The aim of this study was to determine whether LDL particle size is associated with stroke severity and functional outcome in patients with atherothrombotic stroke. Between January 2009 and May 2011, 248 patients with first-episode cerebral infarction who were admitted to our hospital within 7 days after symptom onset were prospectively enrolled. LDL particle size was measured using the nondenaturing polyacrylamide gradient gel electrophoresis assay. Stroke severity was assessed by applying the National Institutes of Health Stroke Scale (NIHSS) at admission. Functional outcome was investigated at 3 months after the index stroke using the modified Rankin Scale (mRS), and poor functional outcome was defined as an mRS score of ≥3. The LDL particle size in the 248 patients was 25.9±0.9 nm (mean±SD). LDL particle size was inversely correlated with the degree of cerebral artery stenosis (p=0.010). Multinomial multivariate logistic analysis revealed that after adjustment for age, sex, and variables with p<0.1 in univariate analysis, LDL particle size was independently and inversely associated with stroke severity (NIHSS score ≥5; reference, NIHSS score 0-2; odds ratio=0.38, p=0.028) and poor functional outcome (odds ratio=0.44, p=0.038). The results of this study demonstrate that small LDL particles are independently correlated with stroke outcomes. LDL particle size is thus a potential biomarker for the prognosis of atherothrombotic stroke.

  9. Platelets mediate oxidized low-density lipoprotein-induced monocyte extravasation and foam cell formation.

    PubMed

    Badrnya, Sigrun; Schrottmaier, Waltraud C; Kral, Julia B; Yaiw, Koon-Chu; Volf, Ivo; Schabbauer, Gernot; Söderberg-Nauclér, Cecilia; Assinger, Alice

    2014-03-01

    A growing body of evidence indicates that platelets contribute to the onset and progression of atherosclerosis by modulating immune responses. We aimed to elucidate the effects of oxidized low-density lipoprotein (OxLDL) on platelet-monocyte interactions and the consequences of these interactions on platelet phagocytosis, chemokine release, monocyte extravasation, and foam cell formation. Confocal microscopy and flow cytometric analysis revealed that in vitro and in vivo stimulation with OxLDL resulted in rapid formation of platelet-monocyte aggregates, with a preference for CD16+ monocyte subsets. This platelet-monocyte interaction facilitated OxLDL uptake by monocytes, in a process that involved platelet CD36-OxLDL interaction, release of chemokines, such as CXC motif ligand 4, direct platelet-monocyte interaction, and phagocytosis of platelets. Inhibition of cyclooxygenase with acetylsalicylic acid and antagonists of ADP receptors, P2Y1 and P2Y12, partly abrogated OxLDL-induced platelet-monocyte aggregates and platelet-mediated lipid uptake in monocytes. Platelets also enhanced OxLDL-induced monocyte transmigration across an endothelial monolayer via direct interaction with monocytes in a transwell assay. Importantly, in LDLR(-/-) mice, platelet depletion resulted in a significant decrease of peritoneal macrophage recruitment and foam cell formation in a thioglycollate-elicited peritonitis model. In platelet-depleted wild-type mice, transfusion of ex vivo OxLDL-stimulated platelets induced monocyte extravasation to a higher extent when compared with resting platelets. Our results on OxLDL-mediated platelet-monocyte aggregate formation, which promoted phenotypic changes in monocytes, monocyte extravasation and enhanced foam cell formation in vitro and in vivo, provide a novel mechanism for how platelets potentiate key steps of atherosclerotic plaque development and plaque destabilization.

  10. Systemic Free Fatty Acid Disposal Into Very Low-Density Lipoprotein Triglycerides

    PubMed Central

    Koutsari, Christina; Mundi, Manpreet S.; Ali, Asem H.; Patterson, Bruce W.; Jensen, Michael D.

    2013-01-01

    We measured the incorporation of systemic free fatty acids (FFA) into circulating very low-density lipoprotein triglycerides (VLDL-TGs) under postabsorptive, postprandial, and walking conditions in humans. Fifty-five men and 85 premenopausal women with BMI 18–24 (lean) and 27–36 kg/m2 (overweight/obese) received an intravenous bolus injection of [1,1,2,3,3-2H5]glycerol (to measure VLDL-TG kinetics) and either [1-14C]palmitate or [9,10-3H]palmitate to determine the proportion of systemic FFA that is converted to VLDL-TG. Experiments started at 0630 h after a 12-h overnight fast. In the postabsorptive protocol, participants rested and remained fasted until 1330 h. In the postprandial protocol, volunteers ingested frequent portions of a fat-free smoothie. In the walking protocol, participants walked on a treadmill for 5.5 h at ∼3× resting energy expenditure. Approximately 7% of circulating FFA was converted into VLDL-TG. VLDL-TG secretion rates (SRs) were not statistically different among protocols. Visceral fat mass was the only independent predictor of VLDL-TG secretion, explaining 33–57% of the variance. The small proportion of systemic FFA that is converted to VLDL-TG can confound the expected relationship between plasma FFA concentration and VLDL-TG SRs. Regulation of VLDL-TG secretion is complex in that, despite a broad spectrum of physiological FFA concentrations, VLDL-TG SRs did not vary based on different acute substrate availability. PMID:23434937

  11. Association of Oxidized Low-Density Lipoprotein With Prognosis of Stroke and Stroke Subtypes.

    PubMed

    Wang, Anxin; Yang, Yuling; Su, Zhaoping; Yue, Wei; Hao, Hongjun; Ren, Lijie; Wang, Yongjun; Cao, Yibin; Wang, Yilong

    2017-01-01

    The association between oxidized low-density lipoprotein (oxLDL) and the long-term prognosis of stroke is unclear. The aim of this study is to investigate whether oxLDL levels contribute to the prognosis of stroke and stroke subtypes. All patients with ischemic stroke were recruited from the SOS-Stroke (Study of Oxidative Stress in Patients With Acute Ischemic Stroke) and classified into 5 different subtypes, according to the TOAST criteria (Trial of Org 10172 in Acute Stroke Treatment). We measured oxLDL levels and followed up with patients at 1 year after stroke onset. We analyzed the association between oxLDL and the clinical outcomes of death and poor functional outcome (modified Rankin Scale score of 3-6) of stroke and different stroke subtypes. Among the 3688 patients included in this study, 293 (7.94%) were deceased at the 1-year follow-up and 1020 (27.66%) had a poor functional outcome. Patients in the highest oxLDL quartile had a higher risk of 1-year stroke mortality (hazard ratio, 1.61; 95% confidence interval, 1.10-2.33; P<0.001) and a poor functional outcome (odds ratio, 1.48; 95% confidence interval, 1.15-1.89; P<0.001) compared with the lowest oxLDL quartile. In the subgroup analyses, oxLDL was only significantly associated with death and poor functional outcome in the large-artery atherosclerosis subgroup (P<0.05) and small-artery occlusion subgroup (P<0.05). High levels of oxLDL were associated with the high risk of death and poor functional outcome within 1 year after stroke onset, especially in large-artery atherosclerosis and small-artery occlusion stroke subtypes. © 2016 American Heart Association, Inc.

  12. Oxidized low density lipoproteins--do we know enough about them?

    PubMed

    Jiang, Xueting; Yang, Zhaohui; Chandrakala, Aluganti Narasimhulu; Pressley, Dawn; Parthasarathy, Sampath

    2011-10-01

    Since the discovery of oxidized low density lipoprotein (Ox-LDL), over 5,000 articles have appeared on the topic with over 400 articles appearing every year during the past decade. LDL contains esterified polyunsaturated fatty acid containing lipids, such as, phosphatidylcholine (PtdCho) and cholesterol esters (CE). Peroxidation of polyunsaturated fatty acid (PUFA) containing lipids has been known for a long time. Numerous studies have documented that peroxidized lipids as well as products derived from their decomposition, particularly aldehydes, have deleterious biological properties. This concept has been exemplified in the study of atherosclerosis. A plethora of in vitro and animal studies, as well as human epidemiological and correlatory studies, have supported the notion that oxidative processes and the formation of Ox-LDL might contribute to atherosclerosis. Yet the negative outcomes of human clinical trials with α-tocopherol and other antioxidants have convinced even staunch supporters of the hypothesis to take a step backwards and reconsider reasons of their failure and suggest alternative approaches. Ox-LDL is a complex mixture of numerous chemical entities, many of them are yet uncharacterized. Why and how it is formed or its nature in vivo is poorly understood. It is recognized by numerous cell surface receptors, which are ubiquitously expressed in many different cell types. These receptors might perform a variety of functions. In addition, components of Ox-LDL might also have favorable effects that are difficult to dissociate from its pathological effects. In this review, the nature of Ox-LDL and potential problems in inhibiting its formation are discussed.

  13. Very low density lipoprotein metabolism in non-ketotic diabetes mellitus: effect of dietary restriction.

    PubMed

    Ginsberg, H; Grundy, S M

    1982-11-01

    We have measured the turnover of very low density lipoprotein (VLDL) triglyceride as well as plasma glucose, insulin and non-esterified fatty acid levels in nine mildly obese non-ketotic, insulinopenic diabetic subjects before and during an energy restricted diet. During the baseline period, subjects were hypertriglyceridaemic, hyperglycaemic and insulinopenic. During dietary restriction (mean weight loss: 2.3 +/- 0.4 kg) plasma triglyceride fell from 8.4 +/- 3.0 to 3.4 +/- 0.89 mmol/l (mean +/- SEM: p less than 0.05), and plasma glucose fell from 13.9 +/- 1.7 to 9.8 +/- 1.4 mmol/l (p less than 0.01). Neither fasting plasma insulin nor the insulin response to an oral glucose load changed. Plasma non-esterified fatty acid concentrations remained constant as well. During the baseline period, the transport rate of VLDL-triglyceride in the diabetic subjects was more than twice that in an age-weighted matched control group (27.4 +/- 2.9 versus 12.1 +/- 0.8 mg/kg ideal body weight per h). The fractional catabolic rates were similar in the two groups (0.20 +/- 0.05 versus 0.21 +/- 0.02/h). During energy restriction of the diabetic subjects, the VLDL-triglyceride transport rate fell to 17.4 +/- 2.9 mg/kg ideal body weight per h (p less than 0.05 versus baseline) while the fractional catabolic rate remained constant at 0.21 +/- 0.06/h (NS versus baseline). These data indicate that the major abnormality in triglyceride metabolism in these non-ketotic, insulinopenic diabetic patients was over-production of VLDL-triglyceride.

  14. Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor.

    PubMed Central

    MacPhee, C H; Moores, K E; Boyd, H F; Dhanak, D; Ife, R J; Leach, C A; Leake, D S; Milliner, K J; Patterson, R A; Suckling, K E; Tew, D G; Hickey, D M

    1999-01-01

    A novel and potent azetidinone inhibitor of the lipoprotein-associated phospholipase A2 (Lp-PLA2), i.e. platelet-activating factor acetylhydrolase, is described for the first time. This inhibitor, SB-222657 (Ki=40+/-3 nM, kobs/[I]=6. 6x10(5) M-1.s-1), is inactive against paraoxonase, is a poor inhibitor of lecithin:cholesterol acyltransferase and has been used to investigate the role of Lp-PLA2 in the oxidative modification of lipoproteins. Although pretreatment with SB-222657 did not affect the kinetics of low-density lipoprotein (LDL) oxidation by Cu2+ or an azo free-radical generator as determined by assay of lipid hydroperoxides (LOOHs), conjugated dienes and thiobarbituric acid-reacting substances, in both cases it inhibited the elevation in lysophosphatidylcholine content. Moreover, the significantly increased monocyte chemoattractant activity found in a non-esterified fatty acid fraction from LDL oxidized by Cu2+ was also prevented by pretreatment with SB-222657, with an IC50 value of 5.0+/-0.4 nM. The less potent diastereoisomer of SB-222657, SB-223777 (Ki=6.3+/-0.5 microM, kobs/[I]=1.6x10(4) M-1.s-1), was found to be significantly less active in both assays. Thus, in addition to generating lysophosphatidylcholine, a known biologically active lipid, these results demonstrate that Lp-PLA2 is capable of generating oxidized non-esterified fatty acid moieties that are also bioactive. These findings are consistent with our proposal that Lp-PLA2 has a predominantly pro-inflammatory role in atherogenesis. Finally, similar studies have demonstrated that a different situation exists during the oxidation of high-density lipoprotein, with enzyme(s) other than Lp-PLA2 apparently being responsible for generating lysophosphatidylcholine. PMID:10024526

  15. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis.

    PubMed

    Schaap, Frank G; Rensen, Patrick C N; Voshol, Peter J; Vrins, Carlos; van der Vliet, Hendrik N; Chamuleau, Robert A F M; Havekes, Louis M; Groen, Albert K; van Dijk, Ko Willems

    2004-07-02

    ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1-5 x 10(8) plaqueforming units/mouse) dose-dependently reduced plasma very low density lipoprotein (VLDL)-TG levels. First, we evaluated whether a reduced hepatic VLDL production contributed to the TG-lowering effect. Ad-apoa5 treatment dose-dependently diminished (29-37%) the VLDL-TG production rate without affecting VLDL particle production, suggesting that apoAV impairs the lipidation of apoB. Second, Ad-apoa5 treatment dose-dependently reduced (68-88%) the postprandial hypertriglyceridemia following an intragastric fat load, suggesting that apoAV also stimulates the lipoprotein lipase (LPL)-dependent clearance of TG-rich lipoproteins. Indeed, recombinant apoAV was found to dose-dependently stimulate LPL activity up to 2.3-fold in vitro. Accordingly, intravenously injected VLDL-like TG-rich emulsions were cleared at an accelerated rate concomitant with the increased uptake of emulsion TG-derived fatty acids by skeletal muscle and white adipose tissue in Ad-apoa5-treated mice. From these data, we conclude that apoAV is a potent stimulator of LPL activity. Thus, apoAV lowers plasma TG by both reducing the hepatic VLDL-TG production rate and by enhancing the lipolytic conversion of TG-rich lipoproteins.

  16. Orange juice decreases low-density lipoprotein cholesterol in hypercholesterolemic subjects and improves lipid transfer to high-density lipoprotein in normal and hypercholesterolemic subjects.

    PubMed

    Cesar, Thais B; Aptekmann, Nancy P; Araujo, Milena P; Vinagre, Carmen C; Maranhão, Raul C

    2010-10-01

    Orange juice (OJ) is regularly consumed worldwide, but its effects on plasma lipids have rarely been explored. This study hypothesized that consumption of OJ concentrate would improve lipid levels and lipid metabolism, which are important in high-density lipoprotein (HDL) function in normolipidemic (NC) and hypercholesterolemic (HCH) subjects. Fourteen HCH and 31 NC adults consumed 750 mL/day OJ concentrate (1:6 OJ/water) for 60 days. Eight control subjects did not consume OJ for 60 days. Plasma was collected before and on the last day for biochemical analysis and an in vitro assay of transfers of radioactively labeled free-cholesterol, cholesteryl esters, phospholipids, and triglycerides from lipoprotein-like nanoemulsions to HDL. Orange juice consumption decreased low-density lipoprotein cholesterol (160 ± 17 to 141 ± 26 mg/dL, P < .01) in the HCH group but not in the NC group. HDL-cholesterol and triglycerides remained unchanged in both groups. Free-cholesterol transfer to HDL increased (HCH: 4.4 ± 2 to 5.6 ± 1%, NC: 3.2 ± 2 to 6.2 ± 1%, P< .05) whereas triglyceride (HCH 4.9 ± 1 to 3.1 ± 1%, NC 4.4 ± 1 to 3.4 ± 1%, P< .05) and phospholipid (HCH 21.6 ± 2 to 18.6 ± 3%, NC 20.2 ± 2 to 18.4 ± 2%, P < .05) transfers decreased in both groups. Cholesteryl-ester transfer decreased only in HCH (3.6 ± 1 to 3.1 ± 1%, P < .05), but not in NC. In control subjects, plasma lipids and transfers were unaltered for 60 days. Thus, by decreasing atherogenic low-density lipoprotein cholesterol in HCH and increasing HDL ability to take up free cholesterol in HCH and NC, OJ may be beneficial to both groups as free-cholesterol transfer to HDL is crucial for cholesterol esterification and reverse cholesterol transport.

  17. 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

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

    2014-01-01

    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

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

    PubMed

    Titov, V N

    2015-06-01

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

  19. Oxidation of serum low-density lipoprotein (LDL) and antioxidant status in young and elderly humans.

    PubMed

    Nakamura, Yukiko K; Read, Marsha H; Elias, Jeffrey W; Omaye, Stanley T

    2006-01-01

    The incidence of atherosclerosis increases with age, as do various indices of free-radical mediated damage, e.g., lipid peroxidation. Because lipid peroxidation plays a prominent role in lipoprotein oxidation, likely a prelude to atherosclerosis, we compared the susceptibility of lipoproteins to oxidation in young (19-30 years) and elderly (59-86 years) groups. Although we found no significant differences in serum malondialdehyde (MDA) or oxidized LDL antibodies (OLAB) between young and elderly lipoproteins, MDA was directly related to OLAB regardless of age (r = 0.322, p = 0.005) and there was a trend for lower OLAB levels (30.5%, p = 0.079) in the elderly compared to the young population. Overall, serum antioxidant status was either similar or greater in the elderly group compared to the young group, likely reflecting antioxidant supplementation by the elderly group. OLAB was inversely related to Vitamin C (r = -0.310, p = 0.008) and Vitamin E intake (r = -0.277, p = 0.018) from foods and supplements. Serum levels of Vitamin C and Vitamin E were significantly higher (18.5%, p = 0.021 and 58.1 %, p < 0.001, respectively) in the elderly group compared to the young group and the ratio of Vitamin E to Vitamin C was significantly higher (30.4%, p = 0.042) in the serum of the elderly group. Oxidation of serum LDL and antioxidant status were not affected by age; however, the ratio of serum Vitamin E to Vitamin C was higher in the elderly group which may affect Vitamin E recycling.

  20. Pectin isolated from prickly pear (Opuntia sp.) modifies low density lipoprotein metabolism in cholesterol-fed guinea pigs.

    PubMed

    Fernandez, M L; Trejo, A; McNamara, D J

    1990-11-01

    The effect of prickly pear soluble fiber on low density lipoprotein (LDL) metabolism was investigated by feeding male guinea pigs either a nonpurified diet containing 0.25% cholesterol (HC diet) or the HC diet + 1% prickly pear pectin (HC-P diet). Plasma cholesterol levels were significantly decreased by the HC-P diet, with a 33% decrease in LDL levels (p less than 0.02) and an increase in LDL density. Hepatic free and esterified cholesterol levels were reduced 40 and 85%, respectively (p less than 0.002), by the HC-P diet. Hepatic microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase levels were not different. 125I-LDL binding to hepatic membranes was increased 1.7-fold by the HC-P diet (p less than 0.001), with receptor affinity (Kd) being unaltered and receptor number (Bmax) being significantly increased (p less than 0.001). These data suggest that prickly pear pectin may act by a mechanism similar to that of bile acid-binding resins in lowering plasma cholesterol levels. The observed reduction in LDL and hepatic cholesterol levels and increase in LDL density and hepatic apolipoprotein B/E receptors are responses suggesting an increased demand on hepatic cholesterol from increased excretion of bile acids and interruption of the enterohepatic circulation.

  1. Medical and psychosocial factors and unfavourable low-density lipoprotein cholesterol control in coronary patients.

    PubMed

    Munkhaugen, John; Sverre, Elise; Otterstad, Jan E; Peersen, Kari; Gjertsen, Erik; Perk, Joep; Gullestad, Lars; Moum, Torbjørn; Dammen, Toril; Husebye, Einar

    2017-01-01

    Objective Understanding the determinants of low-density lipoprotein cholesterol (LDL-C) control constitutes the basis of modelling interventions for optimal lipid control and prognosis. We aim to identify medical and psychosocial (study) factors associated with unfavourable LDL-C control in coronary patients. Methods A cross-sectional explorative study used logistic and linear regression analysis to investigate the association between study factors and LDL-C in 1095 patients, hospitalized with myocardial infarction and/or a coronary revascularization procedure. Data were collected from hospital records, a comprehensive self-report questionnaire, clinical examination and blood samples after 2-36 months follow-up. Results Fifty-seven per cent did not reach the LDL-C target of 1.8 mmol/l at follow-up. Low socioeconomic status and psychosocial factors were not associated with failure to reach the LDL-C target. Statin specific side-effects (odds ratio 3.23), low statin adherence (odds ratio 3.07), coronary artery by-pass graft operation as index treatment (odds ratio 1.95), ≥ 1 coronary event prior to the index event (odds ratio 1.81), female gender (odds ratio 1.80), moderate- or low-intensity statin therapy (odds ratio 1.62) and eating fish < 3 times/week (odds ratio 1.56) were statistically significantly associated with failure to reach the LDL-C target, in adjusted analyses. Only side-effects (standardized β 0.180), low statin adherence ( β 0.209) and moderate- or low-intensity statin therapy ( β 0.228) were associated with LDL-C in continuous analyses. Conclusions Statin specific side-effects, low statin adherence and moderate- or low-intensity statin therapy were the major factors associated with unfavourable LDL-C control. Interventions to improve LDL-C should ensure adherence and prescription of sufficiently potent statins, and address side-effects appropriately.

  2. Oxidized Low Density Lipoprotein Among the Elderly in Qinghai-Tibet Plateau.

    PubMed

    Sakamoto, Ryota; Okumiya, Kiyohito; Wang, Hongxin; Dai, Qingxiang; Fujisawa, Michiko; Wada, Taizo; Imai, Hissei; Kimura, Yumi; Ishimoto, Yasuko; Fukutomi, Eriko; Chen, Wingling; Sasiwongsaroj, Kwanchit; Kato, Emiko; Ge, Ri-Li; Matsubayashi, Kozo

    2015-09-01

    Several environmental factors including hypoxia have been reported to contribute to oxidative stress in individuals living in the highlands. However, little is known about the role of oxidized low-density lipoprotein (ox-LDL) among community-dwelling elderly in the Qinghai-Tibet plateau. The study population comprised 168 community-dwelling elderly subjects aged 60 years or older (male to female ratio, 70:98; mean age, 65.8 years) living in Haiyan County, located 3000 to 3200 m above sea level, 30 km northwest of Xining, Qinghai. The subjects were volunteers who joined a Comprehensive Geriatric Assessment. Plasma ox-LDL was measured in 168 community-dwelling elderly subjects aged 60 years or older (23 Tibetans and 145 Hans) with a monoclonal antibody-based enzyme-linked immunosorbent assay. Mean ox-LDL level was higher among Tibetan elderly than Han elderly (Tibetan, 79.0 ± 29.6 U/L; Han, 62.8 ± 23.5 U/L; P = .003). Tibetan ethnicity was significantly associated with ox-LDL levels after adjusting for LDL cholesterol levels. In addition, high ox-LDL levels (≥70 U/L) were significantly associated with a homeostasis model assessment insulin resistance index of at least 1.6 (odds ratio [OR], 2.82; 95% confidence interval [95% CI], 1.11 to 7.15; P = .029) and ankle brachial pressure index of less than 1.0 (OR, 4.85; 95% CI, 1.14 to 10.00; P = .028), after adjusting for age, sex, and ethnicity. Our findings support the hypothesis that ox-LDL levels are higher among Tibetan elderly highlanders compared with those among Han elderly. As ox-LDL levels can affect insulin resistance and arteriosclerosis, further research is needed to determine how oxidative stress influences the health situation among elderly individuals at high altitudes. Copyright © 2015 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

  3. Multiple mechanisms for inhibition of low density lipoprotein oxidation by novel cyclic nitrone spin traps.

    PubMed

    Thomas, C E; Ohlweiler, D F; Kalyanaraman, B

    1994-11-11

    Oxidation of low density lipoproteins (LDL) may be a critical atherogenic event owing to the diverse array of biologic effects attributed to modified LDL. Recently, we and others have demonstrated that the lipophilic nitrone spin trap alpha-phenyl-N-tert-butyl nitrone (PBN) can inhibit Cu(2+)-dependent LDL oxidation while the related, more hydrophilic analog alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone is ineffective. Because the inhibitory activity of PBN is relatively weak as compared to hydrophobic phenolic antioxidants, we have synthesized a number of cyclic analogues of PBN that encompass a wide range of hydrophobicity and examined their ability to inhibit LDL oxidation in vitro. Formation of a six-membered ring by a bond formed from one methyl of the tert-butyl group to the aromatic ring yielded MDL 101,002, which was 3- and 24-fold more active than PBN against Cu2+ and 2,2'-azobis-2-amidinopropane hydrochloride-dependent oxidation, respectively. The effect of aromatic substituents was examined and, in general, activity positively correlated with hydrophobicity, particularly with Cu2+. Electron spin resonance (ESR) spectroscopy demonstrated that the PBN adduct in oxidized LDL is composed of a mobile component (exposed to the LDL aqueous phase) and an immobilized component, localized in the lipid-protein interface or in the bulk lipid. The most active cyclic nitrones exhibited only highly immobilized adducts, suggesting they are buried within the particle. Studies with MDL 105,185 (which is a chloro-substituted nitrone containing a seven-membered ring rather than six-membered as for MDL 101,002) demonstrated radical trapping in both the lipid and apoprotein fractions. Compounds in which a spirocyclohexyl ring was substituted for the gem-dimethyl methylene (MDL 102,832 and 101,694) formed hydrophobic Cu2+ complexes that were observed in the lipid fraction by ESR. This result was confirmed by fractionation of LDL oxidation reaction mixtures and

  4. Low-density lipoprotein and intracerebral hematoma expansion in daily alcohol users.

    PubMed

    Pletsch, Gayle R; Boehme, Amelia K; Albright, Karen C; Burns, Christopher; Beasley, T Mark; Martin-Schild, Sheryl

    2014-01-01

    Epidemiological studies suggest that the intracerebral hemorrhage (ICH) rate correlates with alcohol consumption. Alcohol leads to elevated blood pressure (BP) and inhibition of platelet aggregation. These factors could promote excessive bleeding. To our knowledge, in the setting of normal liver function tests, there are no studies that have systematically evaluated the relationship between daily alcohol use and hematoma expansion. The aim of this study is to compare the baseline ICH characteristics, frequency of hematoma expansion, and outcomes in patients with ICH who are daily alcohol users with those who are not daily alcohol users. A retrospective chart review was performed on consecutive patients who presented from July 2008 to July 2013 to the Tulane University Hospital in New Orleans, La., USA, with a spontaneous ICH. Ninety-nine patients who met these criteria were admitted. Patients who underwent hematoma evacuation were excluded. Hemorrhage volumes were calculated based on the ABC/2 method. Low-density lipoprotein (LDL) was dichotomized into low (<100 mg/dl) and high (≥100 mg/dl) values. Comparisons were made using t tests, χ(2) and nonparametric equivalents where appropriate. ICH growth in 24 h and LDL were evaluated using linear regression. Of the 226 patients who met inclusion criteria, 20.4% had a history of daily alcohol use. The average age was 61 years (range 19-94), 55.6% of the patients were males, and 67.1% were of African American origin. Daily alcohol use was associated with male gender, lower rate of home antihypertensive, higher presenting BP, and lower platelet counts, but there was no difference in ICH characteristics, ICH growth, or clinical outcome. Daily alcohol use in patients with a low LDL level was associated with supratentorial location and trends for lower baseline Glasgow Coma Scale score, higher ICH score, and follow-up ICH volume, but no significant difference in significant hematoma expansion or clinical outcome except for

  5. The Potential Protective Effects of Phenolic Compounds against Low-density Lipoprotein Oxidation.

    PubMed

    Amarowicz, Ryszard; Pegg, Ronald B

    2017-01-01

    The exact mechanism(s) of atherosclerosis in humans remains elusive, but one theory hypothesizes that this deleterious process results from the oxidative modification of low-density lipoprotein (LDL). Research suggests that foods rich in dietary phenolic compounds with antioxidant activity can mitigate the extent of LDL oxidation in vivo. With regard to the different classes of flavonoids, there appears to be a structurefunction relationship between the various moieties/constituents attached to the flavonoids' three ring system and their impact at retarding LDL oxidation. This article summarizes the findings to date of both in vitro and in vivo studies using foods or phenolic extracts isolated from foodstuffs at inhibiting the incidence of LDL oxidation. Three bases: SCOPUS, Web Science, and PubMed were used for search. An often used method for the determination of antioxidant properties of natural phenolic compounds is the LDL oxidation assay. LDLs are isolated from human plasma and their oxidation is induced by Cu2+ ions or 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH). The sample is incubated with a phenolic extract or individual/isolated phenolic compounds. LDL oxidation is then monitored by various chemical methods (e.g., measurement of the generation of conjugated dienes and trienes). This technique confirmed the antioxidant properties of several extracts as obtained from plant material (e.g., grapes, berries, orange, grapefruit, coffee, tea, chocolate, olives, nuts) as well as the individual phenolic compounds (e.g., luteolinidin, apigenidin, caffeic acid, chlorogenic acid, catechin, quercetin, rutin). Several studies in vivo confirmed protective effects of phenolic compounds against LDL oxidation. They covered the healthy subjects with hyperlipidaemia, overweight, obesity, metabolic syndrome, heavy smokers, patients receiving haemodialysis, patients with peripheral vascular disease, and subjects at high cardiovascular risk. The studies comprise

  6. Apolipoprotein E mediates enhanced plasma high-density lipoprotein cholesterol clearance by low-dose streptococcal serum opacity factor via hepatic low-density lipoprotein receptors in vivo.

    PubMed

    Rosales, Corina; Tang, Daming; Gillard, Baiba K; Courtney, Harry S; Pownall, Henry J

    2011-08-01

    Recombinant streptococcal serum opacity factor (rSOF) mediates the in vitro disassembly of human plasma high-density lipoprotein (HDL) into lipid-free apolipoprotein (apo) A-I, a neo-HDL that is cholesterol poor, and a cholesteryl ester-rich microemulsion (CERM) containing apoE. Given the occurrence of apoE on the CERM, we tested the hypothesis that rSOF injection into mice would reduce total plasma cholesterol clearance via apoE-dependent hepatic low-density lipoprotein receptors (LDLR). rSOF (4 μg) injection into wild-type C57BL/6J mice formed neo-HDL, CERM, and lipid-free apoA-I, as observed in vitro, and reduced plasma total cholesterol (-43%, t(1/2)=44±18 minutes) whereas control saline injections had a negligible effect. Similar experiments with apoE(-/-) and LDLR(-/-) mice reduced plasma total cholesterol ≈0% and 20%, respectively. rSOF was potent; injection of 0.18 μg of rSOF produced 50% of maximum reduction of plasma cholesterol 3 hours postinjection, corresponding to a ≈0.5-mg human dose. Most cholesterol was cleared hepatically (>99%), with rSOF treatment increasing clearance by 65%. rSOF injection into mice formed a CERM that was cleared via hepatic LDLR that recognize apoE. This reaction could provide an alternative mechanism for reverse cholesterol transport.

  7. Association between moderately oxidized low-density lipoprotein and high-density lipoprotein particle subclass distribution in hemodialyzed and post-renal transplant patients.

    PubMed

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

    2011-05-01

    Disturbances in the metabolism of lipoprotein profiles and oxidative stress in hemodialyzed (HD) and post-renal transplant (Tx) patients are proatherogenic, but elevated concentrations of plasma high-density lipoprotein (HDL) reduce the risk of cardiovascular disease. We investigated the concentrations of lipid, lipoprotein, HDL particle, oxidized low-density lipoprotein (ox-LDL) and anti-ox-LDL, and paraoxonase-1 (PON-1) activity in HD (n=33) and Tx (n=71) patients who were non-smokers without active inflammatory disease, liver disease, diabetes, or malignancy. HD patients had moderate hypertriglyceridemia, normocholesterolemia, low HDL-C, apolipoprotein A-I (apoA-I) and HDL particle concentrations as well as PON-1 activity, and increased ox-LDL and anti-ox-LDL levels. Tx patients had hypertriglyceridemia, hypercholesterolemia, moderately decreased HDL-C and HDL particle concentrations and PON-1 activity, and moderately increased ox-LDL and anti-ox-LDL levels as compared to the reference, but ox-LDL and anti-ox-LDL levels and PON-1 activity were more disturbed in HD patients. However, in both patient groups, lipid and lipoprotein ratios (total cholesterol (TC)/HDL-C, LDL-C/HDL-C, triglyceride (TG)/HDL-C, HDL-C/non-HDL-C, apoA-I/apoB, HDL-C/apoA-I, TG/HDL) were atherogenic. The Spearman's rank coefficient test showed that the concentration of ox-LDL correlated positively with HDL particle level (R=0.363, P=0.004), and negatively with TC (R=-0.306, P=0.012), LDL-C (R=-0.283, P=0.020), and non-HDL-C (R=-0.263, P=0.030) levels in Tx patients. Multiple stepwise forward regression analysis in Tx patients demonstrated that ox-LDL concentration, as an independent variable, was associated significantly positively with HDL particle level. The results indicated that ox-LDL and decreased PON-1 activity in Tx patients may give rise to more mildly-oxidized HDLs, which are less stable, easily undergo metabolic remodeling, generate a greater number of smaller pre-β-HDL particles

  8. Pharmaceutical stabilization of mast cells attenuates experimental atherogenesis in low-density lipoprotein receptor-deficient mice

    PubMed Central

    Wang, Jing; Sjöberg, Sara; Tia, Viviane; Secco, Blandine; Chen, Han; Yang, Min; Sukhova, Galina K.; Shi, Guo-Ping

    2013-01-01

    Mast cells (MCs) contribute to atherogenesis by releasing pro-inflammatory mediators to activate vascular cells and other inflammatory cells. This study examined whether MC activation or stabilization affects diet-induced atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr−/−) mice. When Ldlr−/− mice consumed an atherogenic diet for 3 or 6 months, MC activation with compound 48/80 (C48/80) increased aortic arch intima and total lesion areas, and plasma total cholesterol, LDL, and triglyceride levels, whereas MC stabilization with cromolyn reduced these parameters. There were significant differences in arch intima and total lesion areas, and plasma total cholesterol, LDL, and triglyceride levels between C48/80-treated and cromolyn-treated mice. To examine a therapeutic application of cromolyn in atherosclerosis, we fed Ldlr−/− mice an atherogenic diet for 3 months followed by giving mice cromolyn for additional 3 months. Cromolyn did not affect aortic arch intima area, but significantly reduced lipid deposition in the thoracic-abdominal aortas. In aortic arches, however, cromolyn treatment significantly reduced lesion contents of Mac-3+ macrophages, CD4+ T cells, activated MCs, and lesion cell proliferation. While plasma total cholesterol and LDL levels increased and high-density lipoprotein (HDL) levels decreased from 3 months to 6 months of an atherogenic diet, cromolyn treatment decreased significantly plasma total cholesterol, LDL, and triglyceride levels and increased HDL levels above those of 3-month time point. These observations demonstrate that MC stabilization reduces lesion inflammation, ameliorates plasma lipid profiles, and may serve as a potential therapy for this cardiovascular disease. PMID:23880180

  9. Human pericoronary adipose tissue as storage and possible supply site for oxidized low-density lipoprotein and high-density lipoprotein in coronary artery.

    PubMed

    Uchida, Yasumi; Uchida, Yasuto; Shimoyama, Ei; Hiruta, Nobuyuki; Kishimoto, Toshihoko; Watanabe, Soichiro

    2017-01-01

    Thickening of the pericoronary adipose tissue (PCAT) is a proven risk factor for coronary artery disease, but it is poorly understood whether PCAT stores pro-atherogenic substances with oxidized low-density lipoprotein (oxLDL) and low-density lipoprotein (LDL), and an anti-atherogenic substance with high-density lipoprotein (HDL) and supply them to the coronary intima. Using immunohistochemical techniques, the localization of oxLDL, LDL and HDL in PCAT and its adjacent coronary segments was examined in 30 epicardial coronary arteries excised from 11 human autopsy cases. PCAT stored oxLDL and HDL in all, but LDL rarely, in 77 specimens examined, irrespective of the presence or absence of coronary plaques and underlying disease. The percentage (%) incidence of oxLDL, HDL and LDL deposits in intima was, respectively, 28, 10, 35 in 29 normal segments, 80 (p<0.05 vs. normal segments), 12, 75 in 19 white plaques (growth stage), 57, 36, 90 in 15 yellow plaques without necrotic core (NC; mature stage), and 40, 21, 100 (p<0.05 vs. normal segments) in 14 yellow plaques with NC (end-stage of maturation) as classified by angioscopy and histology. In coronary intima, oxLDL deposited in either a dotted or diffuse pattern whereas HDL and LDL showed diffuse patterns. Dotted oxLDL deposits were contained in CD68(+)-macrophages traversing the border of PCAT and adventitia, external and internal elastic laminae. Diffuse oxLDL and HDL deposits colocalized with intimal vasa vasorum. The results suggested that, as a hitherto unrecognized supplying route, the human PCAT stores oxLDL and HDL and oxLDL is supplied to coronary intima either by CD68(+)-macrophages or vasa vasorum and HDL by vasa vasorum, and that deposition of oxLDL and HDL in the intima increased with plaque growth but the former decreased while the latter increased further with plaque maturation. Molecular therapy targeting PCAT before plaque maturation could be effective in preventing atherosclerosis. Copyright © 2016

  10. Intermittent hypoxia and hypercapnia induce pulmonary artery atherosclerosis and ventricular dysfunction in low density lipoprotein receptor deficient mice.

    PubMed

    Douglas, Robert M; Bowden, Karen; Pattison, Jennifer; Peterson, Alexander B; Juliano, Joseph; Dalton, Nancy D; Gu, Yusu; Alvarez, Erika; Imamura, Toshihiro; Peterson, Kirk L; Witztum, Joseph L; Haddad, Gabriel G; Li, Andrew C

    2013-12-01

    Patients with obstructive sleep apnea, who experience episodic hypoxia and hypercapnia during sleep, often demonstrate increased inflammation, oxidative stress, and dyslipidemia. We hypothesized that sleep apnea patients would be predisposed to the development of atherosclerosis. To dissect the mechanisms involved, we developed an animal model in mice whereby we expose mice to intermittent hypoxia/hypercapnia (IHH) in normobaric environments. Two- to three-month-old low-density lipoprotein receptor deficient (Ldlr(-/-)) mice were fed a high-fat diet for 8 or 16 wk while being exposed to IHH for either 10 h/day or 24 h/day. Plasma lipid levels, pulmonary artery and aortic atherosclerotic lesions, and cardiac function were then assayed. Surprisingly, atherosclerosis in the aorta of IHH mice was similar compared with controls. However, in IHH mice, atherosclerosis was markedly increased in the trunk and proximal branches of the pulmonary artery of exposed mice; even though plasma cholesterol and triglycerides were lower than in controls. Hemodynamic analysis revealed that right ventricular maximum pressure and isovolumic relaxation constant were significantly increased in IHH exposed mice and left ventricular % fractional shortening was reduced. In conclusion, 1) Intermittent hypoxia/hypercapnia remarkably accelerated atherosclerotic lesions in the pulmonary artery of Ldlr(-/-) mice and 2) increased lesion formation in the pulmonary artery was associated with right and left ventricular dysfunction. These findings raise the possibility that patients with obstructive sleep apnea may be susceptible to atherosclerotic disease in the pulmonary vasculature, an observation that has not been previously recognized.

  11. Direct adsorption of low-density lipoprotein and lipoprotein(a) from whole blood: results of the first clinical long-term multicenter study using DALI apheresis.

    PubMed

    Bosch, T; Lennertz, A; Schenzle, D; Dräger, J

    2002-01-01

    Direct adsorption of lipoproteins (DALI) is the first low-density lipoprotein (LDL)-apheresis technique by which atherogenic LDL and lipoprotein(a) (Lp(a)) can be selectively removed from whole blood without plasma separation. The present study was performed to evaluate the efficacy, selectivity and safety of long-term DALI apheresis. Sixty-three hypercholesterolemic coronary patients were treated by weekly DALI sessions. Initial LDL-cholesterol (C) plasma levels averaged 238 +/- 87 mg/dl (range 130-681 mg/dl). On average, 34 sessions (1-45) were performed processing 1.5 patient blood volumes. The primary aim was to acutely reduce LDL-C by >or=60% per session. To this end, three different adsorber sizes could be employed, i.e., DALI 500, 750, and 1000, which were used in 4, 73, and 23% of the 2156 sessions, respectively. On average, 7387 ml of blood were processed in 116 min per session. This resulted in the following mean acute changes: LDL-C 198 --> 63 mg/dl (-69%), Lp(a) 86 --> 32 mg/dl (-64%), triglycerides 185 --> 136 mg/dl (-27%). HDL-C (-11%) and fibrinogen (-15%) were not significantly influenced. The mean long-term reduction of LDL-C was 42% compared to baseline while HDL-C slightly increased in the long run (+4%). The selectivity of LDL removal was good as recoveries of albumin, immunoglobulins, and other proteins exceeded 85%. Ninety-five percent of 2156 sessions were completely uneventful. The most frequent adverse effects were hypotension (1.2% of sessions) and paresthesia (1.1%), which were probably due to citrate anticoagulation. Access problems had to be overcome in 1.5%, adsorber and hardware problems in 0.5% of the sessions. In this multicenter long-term study, DALI apheresis proved to be an efficient, safe, and easy procedure for extracorporeal LDL and Lp(a) elimination.

  12. NG2 Proteoglycan Ablation Reduces Foam Cell Formation and Atherogenesis via Decreased Low-Density Lipoprotein Retention by Synthetic Smooth Muscle Cells.

    PubMed

    She, Zhi-Gang; Chang, Yunchao; Pang, Hong-Bo; Han, Wenlong; Chen, Hou-Zao; Smith, Jeffrey W; Stallcup, William B

    2016-01-01

    Obesity and hyperlipidemia are critical risk factors for atherosclerosis. Because ablation of NG2 proteoglycan in mice leads to hyperlipidemia and obesity, we investigated the impact of NG2 ablation on atherosclerosis in apoE null mice. Immunostaining indicates that NG2 expression in plaque, primarily by synthetic smooth muscle cells, increases during atherogenesis. NG2 ablation unexpectedly results in decreased (30%) plaque development, despite aggravated obesity and hyperlipidemia. Mechanistic studies reveal that NG2-positive plaque synthetic smooth muscle cells in culture can sequester low-density lipoprotein to enhance foam-cell formation, processes in which NG2 itself plays direct roles. In agreement with these observations, low-density lipoprotein retention and lipid accumulation in the NG2/ApoE knockout aorta is 30% less than that seen in the control aorta. These results indicate that synthetic smooth muscle cell-dependent low-density lipoprotein retention and foam cell formation outweigh obesity and hyperlipidemia in promoting mouse atherogenesis. Our study sheds new light on the role of synthetic smooth muscle cells during atherogenesis. Blocking plaque NG2 or altering synthetic smooth muscle cells function may be promising therapeutic strategies for atherosclerosis. © 2015 American Heart Association, Inc.

  13. The effect of low-density lipoprotein apheresis on ocular microcirculation in patients with hypercholesterolaemia: a pilot study.

    PubMed

    Terai, Naim; Julius, Ulrich; Haustein, Michael; Spoerl, Eberhard; Pillunat, Lutz E

    2011-03-01

    To investigate the effect of low-density lipoprotein (LDL) apheresis on ocular microcirculation in patients with hypercholesterolaemia. Six patients with hypercholesterolaemia were included in this study. The diameter of retinal vessels was measured continuously with the retinal vessel analyser before and after LDL apheresis. After baseline assessment a monochromatic luminance flicker was applied to evoke retinal vasodilation. Flicker response was then analysed 50, 70 and 120 s after baseline measurement. In addition, cholesterol, high-density lipoprotein, LDL and triglyceride levels were obtained to find a possible correlation between changes in retinal vessel diameter and lipid metabolism before and after apheresis. The mean diameter of the arterioles at baseline was 107.6±2.1 μm and the mean diameter of the venules at baseline was 132.8±3.2 μm. The diameter of the arterioles after apheresis increased to 111.2±2.3 μm after 50 s, 113.2±2.6 μm after 70 s and 113.7±2.6 μm after 120 s, showing a trend to statistical significance at all time points (p=0.046, p=0.028 and p=0.028, respectively). The mean diameter of the venules after apheresis increased to 138.8±5.9 μm after 50 s, 139.8±6.3 μm after 70 s and 141.2±6.0 μm after 120 s, showing a trend to statistical significance at all time points (all p=0.028). Changes in retinal vascular diameter seem to be associated with the systemic effect of a single LDL apheresis. Vasodilatation of the arterioles and the venules improved after LDL apheresis, indicating an improvement of ocular perfusion in patients with hypercholesterolaemia.

  14. The mechanism of oxidation-induced low-density lipoprotein aggregation: an analogy to colloidal aggregation and beyond?

    PubMed Central

    Xu, S; Lin, B

    2001-01-01

    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 aggregates branch and interact with one another, forming fractals. In the fusion stage, spatially adjacent nucleation units in the fractal fuse into curved membrane surfaces, which, in turn, fuse into multilamellar or unilamellar vesicles. Alternatively, some adjacent nucleation units in the fractals assemble in a straight line and form rods. Subsequently, the rods flatten out into rough and then into smooth ribbons. Occasionally, tubular membrane vesicles are formed from the fractals. The aggregation stage seems to be analogous to colloidal aggregation and amyloid fiber formation. The fusion stage seems to be characteristic of the lipid-rich lipoproteins and is beyond colloidal aggregation and amyloid fiber formation. PMID:11566810

  15. [Consecutive formation of the functions of high-, low-density and very-low-density lipoproteins during phylogenesis. Unique algorithm of the effects of lipid-lowering drugs].

    PubMed

    Titov, V N; Rozhkova, T A; Aripovsky, A V

    2015-01-01

    During phylogenesis, all fatty acids (FA) were initially transported to cells by apoA-I high-density lipoproteins (HDL) in polar lipids. Later, active cellular uptake of saturated, monoenoic and unsaturated FA occurred via triglycerides (TG) in low-density lipoproteins (LDL). Active uptake of polyenoic FA (PUFA) required the following: a) PUFA re-esterified from polar phospholipids into nonpolar cholesteryl polyesters (poly-CLE), b) a novel protein, cholesteryl ester transfer protein (CETP), initiated poly-CLE transformation from HDL to LDL. CETP formed blood HDL-CETP-LDL complexes in which poly-CLE spontaneously came from polar lipids of TG in HDL to nonpolar TG in LDL. Then ligand LDLs formed and the cells actively absorbed PUFA via apoB-100 endocytosis. Some animal species (rats, mice, dogs) developed a spontaneous CETP-minus mutation followed by population death from atherosclerosis. However, there was another active CETP-independent uptake formed during phylogenesis; the cells internalized poly-CLE in HDL. Since apoA-I had no domain-ligand, another apoE/A-I ligand formed; the cells began synthesizing apoE/A-1 receptors. In cells of rabbits and primates absorbed cells PUFA consecutively: HDL-->LDL-->apoB-100 endocytosis; those of rats and dogs did HDL directly: HDL-->anoE/A-I endocytosis. In the rabbits, CETP was high, apoE in HDL was low, and the animals were sensitive to exogenous hypercholesterolemia. In the rats, CETP was low and ApoE in HDL-was high, and the animals were resistant to hypercholesterolemia. Reduced bioavailability of PUFA during their consecutive cellular uptake and develdpment of intercellular PUFA deficiency are fundamental to the pathogenesis of atherosclerosis.

  16. Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Aβ uptake and degradation by astrocytes.

    PubMed

    Basak, Jacob M; Verghese, Philip B; Yoon, Hyejin; Kim, Jungsu; Holtzman, David M

    2012-04-20

    Accumulation of the amyloid β (Aβ) peptide within the brain is hypothesized to be one of the main causes underlying the pathogenic events that occur in Alzheimer disease (AD). Consequently, identifying pathways by which Aβ is cleared from the brain is crucial for better understanding of the disease pathogenesis and developing novel therapeutics. Cellular uptake and degradation by glial cells is one means by which Aβ may be cleared from the brain. In the current study, we demonstrate that modulating levels of the low-density lipoprotein receptor (LDLR), a cell surface receptor that regulates the amount of apolipoprotein E (apoE) in the brain, altered both the uptake and degradation of Aβ by astrocytes. Deletion of LDLR caused a decrease in Aβ uptake, whereas increasing LDLR levels significantly enhanced both the uptake and clearance of Aβ. Increasing LDLR levels also enhanced the cellular degradation of Aβ and facilitated the vesicular transport of Aβ to lysosomes. Despite the fact that LDLR regulated the uptake of apoE by astrocytes, we found that the effect of LDLR on Aβ uptake and clearance occurred in the absence of apoE. Finally, we provide evidence that Aβ can directly bind to LDLR, suggesting that an interaction between LDLR and Aβ could be responsible for LDLR-mediated Aβ uptake. Therefore, these results identify LDLR as a receptor that mediates Aβ uptake and clearance by astrocytes, and provide evidence that increasing glial LDLR levels may promote Aβ degradation within the brain.

  17. Low-density Lipoprotein Receptor Represents an Apolipoprotein E-independent Pathway of Aβ Uptake and Degradation by Astrocytes*

    PubMed Central

    Basak, Jacob M.; Verghese, Philip B.; Yoon, Hyejin; Kim, Jungsu; Holtzman, David M.

    2012-01-01

    Accumulation of the amyloid β (Aβ) peptide within the brain is hypothesized to be one of the main causes underlying the pathogenic events that occur in Alzheimer disease (AD). Consequently, identifying pathways by which Aβ is cleared from the brain is crucial for better understanding of the disease pathogenesis and developing novel therapeutics. Cellular uptake and degradation by glial cells is one means by which Aβ may be cleared from the brain. In the current study, we demonstrate that modulating levels of the low-density lipoprotein receptor (LDLR), a cell surface receptor that regulates the amount of apolipoprotein E (apoE) in the brain, altered both the uptake and degradation of Aβ by astrocytes. Deletion of LDLR caused a decrease in Aβ uptake, whereas increasing LDLR levels significantly enhanced both the uptake and clearance of Aβ. Increasing LDLR levels also enhanced the cellular degradation of Aβ and facilitated the vesicular transport of Aβ to lysosomes. Despite the fact that LDLR regulated the uptake of apoE by astrocytes, we found that the effect of LDLR on Aβ uptake and clearance occurred in the absence of apoE. Finally, we provide evidence that Aβ can directly bind to LDLR, suggesting that an interaction between LDLR and Aβ could be responsible for LDLR-mediated Aβ uptake. Therefore, these results identify LDLR as a receptor that mediates Aβ uptake and clearance by astrocytes, and provide evidence that increasing glial LDLR levels may promote Aβ degradation within the brain. PMID:22383525

  18. Activation of sonic hedgehog signaling attenuates oxidized low-density lipoprotein-stimulated brain microvascular endothelial cells dysfunction in vitro.

    PubMed

    Jiang, Xiu-Long; Chen, Ting; Zhang, Xu

    2015-01-01

    The study was performed to investigate the role of sonic hedgehog (SHH) in the oxidized low-density lipoprotein (oxLDL)-induced blood-brain barrier (BBB) disruption. The primary mouse brain microvascular endothelial cells (MBMECs) were exposed to oxLDL. The results indicated that treatment of MBMECs with oxLDL decreased the cell viability, and oxidative stress was involved in oxLDL-induce MBMECs dysfunction with increasing intracellular ROS and MDA formation as well as decreasing NO release and eNOS mRNA expression. In addition, SHH signaling components, such as SHH, Smo and Gli1, mRNA and protein levels were significantly decreased after incubation with increasing concentrations of oxLDL. Treatment with oxLDL alone or SHH loss-of-function significantly increased the permeability of MBMECs, and overexpression of SHH attenuated oxLDL-induced elevation of permeability in MBMECs. Furthermore, SHH gain-of-function could reverse oxLDL-induced apoptosis through inhibition caspase3 and caspase8 levels in MBMECs. Taken together, these results demonstrated that the suppression of SHH in MBMECs might contribute to the oxLDL-induced disruption of endothelial barrier. However, the overexpression of SHH could reverse oxLDL-induced endothelial cells dysfunction in vitro.

  19. Z-Scan Analysis: a New Method to Determine the Oxidative State of Low-Density Lipoprotein and Its Association with Multiple Cardiometabolic Biomarkers

    NASA Astrophysics Data System (ADS)

    de Freitas, Maria Camila Pruper; Figueiredo Neto, Antonio Martins; Giampaoli, Viviane; da Conceição Quintaneiro Aubin, Elisete; de Araújo Lima Barbosa, Milena Maria; Damasceno, Nágila Raquel Teixeira

    2016-04-01

    The great atherogenic potential of oxidized low-density lipoprotein has been widely described in the literature. The objective of this study was to investigate whether the state of oxidized low-density lipoprotein in human plasma measured by the Z-scan technique has an association with different cardiometabolic biomarkers. Total cholesterol, high-density lipoprotein cholesterol, triacylglycerols, apolipoprotein A-I and apolipoprotein B, paraoxonase-1, and glucose were analyzed using standard commercial kits, and low-density lipoprotein cholesterol was estimated using the Friedewald equation. A sandwich enzyme-linked immunosorbent assay was used to detect electronegative low-density lipoprotein. Low-density lipoprotein and high-density lipoprotein sizes were determined by Lipoprint® system. The Z-scan technique was used to measure the non-linear optical response of low-density lipoprotein solution. Principal component analysis and correlations were used respectively to resize the data from the sample and test association between the θ parameter, measured with the Z-scan technique, and the principal component. A total of 63 individuals, from both sexes, with mean age 52 years (±11), being overweight and having high levels of total cholesterol and low levels of high-density lipoprotein cholesterol, were enrolled in this study. A positive correlation between the θ parameter and more anti-atherogenic pattern for cardiometabolic biomarkers together with a negative correlation for an atherogenic pattern was found. Regarding the parameters related with an atherogenic low-density lipoprotein profile, the θ parameter was negatively correlated with a more atherogenic pattern. By using Z-scan measurements, we were able to find an association between oxidized low-density lipoprotein state and multiple cardiometabolic biomarkers in samples from individuals with different cardiovascular risk factors.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  1. An increase in lipoprotein oxidation and endogenous lipid peroxides in serum of obese women.

    PubMed

    Mutlu-Türkoğlu, U; Oztezcan, S; Telci, A; Orhan, Y; Aykaç-Toker, G; Sivas, A; Uysal, M

    2003-02-01

    Endogenous malondialdehyde and diene conjugate levels, the susceptibility of apolipoprotein B-containing lipoproteins to copper-induced lipid peroxidation, and antibody titer against oxidized low-density lipoproteins were increased, but serum antioxidant activity was unchanged in obese women. Serum cholesterol, low-density lipoproteincholesterol, and trigliceride levels were also elevated, but high-density lipoprotein-cholesterol levels remained unchanged in obese women. In vitro, oxidation of apolipoprotein B-containing lipoproteins and levels of antibody against oxidized low-density lipoprotein correlated with body mass index, serum total cholesterol, and low-density lipoproteincholesterol levels in obese women. These results indicate that obesity is associated with increases in endogenous lipid peroxides, oxidation of low-density lipoproteins, and lipids in serum.

  2. Alpinetin enhances cholesterol efflux and inhibits lipid accumulation in oxidized low-density lipoprotein-loaded human macrophages.

    PubMed

    Jiang, Zhengming; Sang, Haiqiang; Fu, Xin; Liang, Ying; Li, Ling

    2015-01-01

    Alpinetin is a natural flavonoid abundantly present in the ginger family. Here, we investigated the effect of alpinetin on cholesterol efflux and lipid accumulation in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages and human peripheral blood monocyte-derived macrophages (HMDMs). After exposing THP-1 macrophages to alpinetin, cholesterol efflux was determined by liquid scintillator. The mRNA and protein levels of peroxisome proliferator-activated receptor gamma (PPAR-γ), liver X receptor alpha (LXR-α), ATP-binding cassette transporter A1 (ABCA1), and ABCG1 and scavenger receptor class B member 1 were determined by reverse-transcriptase PCR (RT-PCR) and Western blot analysis, respectively. Alpinetin promoted apolipoprotein A-I- and high-density-lipoprotein-mediated cholesterol efflux and elevated PPAR-γ and LXR-α mRNA and protein expression in a dose-dependent fashion in ox-LDL-treated THP-1 macrophages and HMDMs. Small interfering RNA-mediated silencing of PPAR-γ or LXR-α dose dependently reversed alpinetin-increased cholesterol efflux in THP-1 macrophages, indicating the involvement of PPAR-γ and LXR-α in alpinetin-promoted cholesterol efflux. Alpinetin inhibited ox-LDL-induced lipid accumulation and enhanced the expression of ABCA1 and ABCG1 mRNA and protein, which was reversed by specific knockdown of PPAR-γ or LXR-α. Taken together, our results reveal that alpinetin exhibits positive effects on cholesterol efflux and inhibits ox-LDL-induced lipid accumulation, which might be through PPAR-γ/LXR-α/ABCA1/ABCG1 pathway.

  3. Both inherited susceptibility and environmental exposure determine the low-density lipoprotein-subfraction pattern distribution in healthy Dutch families

    SciTech Connect

    Graaf, J. de; Swinkels, D.W.; Haan, A.F.J. de; Demacker, P.N.M.; Stalenhoef, A.F.H. )

    1992-12-01

    A lipoprotein profile characterized by a predominance of small, dense, low-density lipoprotein (LDL) particles has been associated with an increased risk of atherosclerosis. To investigate whether genetic factors are involved in determining this heavy LDL subfraction pattern, this study was undertaken with the aim of resolving the effects that major genes, multifactorial heritability, and environmental exposures have on the LDL subfraction pattern. In a random sample of 19 healthy Dutch families including 162 individuals, the distribution of the LDL subfraction pattern was determined by density gradient ultracentrifugation. For each subject a specific LDL subfraction profile was observed, characterized by the relative contribution of the three major LDL subfractions - LDL1 (d = 1.030-1.033 g/ml), LDL2 (d = 1.033-1.040 g/ml), and LDL3 (d = 1.040-1.045 g/ml) - to total LDL. A continuous variable, parameter K, was defined to characterize each individual LDL subfraction pattern. Complex segregation analysis of this quantitative trait, under a model which includes a major locus, polygenes, and both common and random environment, was applied to analyze the distribution of the LDL subfraction pattern in these families. The results indicate that the LDL subfraction pattern, described by parameter K, is controlled by a major autosomal, highly penetrant, recessive allele with a population frequency of .19 and an additional multifactorial inheritance component. The results indicate that genetic influences as well as environmental exposure, sex, age and hormonal status in women are important in determining the distribution of the LDL subfraction patterns in this population and that these influences may contribute to the explanation of familial clustering of coronary heart disease. 40 refs., 3 figs., 8 tabs.

  4. Omega-3 fatty acid ethyl ester supplementation decreases very-low-density lipoprotein triacylglycerol secretion in obese men.

    PubMed

    Wong, Annette T Y; Chan, Dick C; Ooi, Esther M M; Ng, Theodore W K; Watts, Gerald F; Barrett, P Hugh R

    2013-03-13

    Dysregulated VLDL-TAG (very-low-density lipoprotein triacylglycerol) metabolism in obesity may account for hypertriacylglycerolaemia and increased cardiovascular disease. ω-3 FAEEs (omega-3 fatty acid ethyl esters) decrease plasma TAG and VLDL concentrations, but the mechanisms are not fully understood. In the present study, we carried out a 6-week randomized, placebo-controlled study to examine the effect of high-dose ω-3 FAEE supplementation (3.2 g/day) on the metabolism of VLDL-TAG in obese men using intravenous administration of d5-glycerol. We also explored the relationship of VLDL-TAG kinetics with the metabolism of VLDL-apo (apolipoprotein) B-100 and HDL (high-density lipoprotein)-apoA-I. VLDL-TAG isotopic enrichment was measured using gas chromatography-mass spectrometry. Kinetic parameters were derived using a multicompartmental model. Compared with placebo, ω-3 FAEE supplementation significantly lowered plasma concentrations of total (-14%, P<0.05) and VLDL-TAG (-32%, P<0.05), as well as hepatic secretion of VLDL-TAG (-32%, P<0.03). The FCR (fractional catabolic rate) of VLDL-TAG was not altered by ω-3 FAEEs. There was a significant association between the change in secretion rates of VLDL-TAG and VLDL-apoB-100 (r=0.706, P<0.05). However, the change in VLDL-TAG secretion rate was not associated with change in HDL-apoA-I FCR (r=0.139, P>0.05). Our results suggest that the TAG-lowering effect of ω-3 FAEEs is associated with the decreased VLDL-TAG secretion rate and hence lower plasma VLDL-TAG concentration in obesity. The changes in VLDL-TAG and apoB-100 kinetics are closely coupled.

  5. Olmesartan Attenuates the Impairment of Endothelial Cells Induced by Oxidized Low Density Lipoprotein through Downregulating Expression of LOX-1

    PubMed Central

    Zhang, Hua; Ma, Genshan; Yao, Yuyu; Qian, Huidong; Li, Weizhang; Chen, Xinjun; Jiang, Wenlong; Zheng, Ruolong

    2012-01-01

    Oxidized low density lipoprotein (ox-LDL) and its receptor, lectin-Like ox-LDL receptor-1 (LOX-1), play important roles in the development of endothelial injuries. Olmesartan can protect endothelial cells from the impairment caused by various pathological stimulations. In the present study we investigated whether olmesartan decreased the impairment of endothelial cells induced by ox-LDL by exerting its effects on LOX-1 both in vitro and in vivo. Incubation of cultured endothelial cells of neonatal rats with ox-LDL for 24 h or infusion of ox-LDL in mice for 3 weeks led to the remarkable impairment of endothelial cells, including increased lactate dehydrogenase synthesis, phosphorylation of p38 mitogen-activated protein kinases (p38 MAPK) and expression of apoptotic genes such as B-cell leukemia/lymphoma 2 (Bcl-2)-associated X protein (Bax) and caspase-3. Simultaneously, the cell vitality and expression of Bcl-2 gene were greatly reduced. All these effects, however, were significantly suppressed by the treatment with olmesartan. Furthermore, ox-LDL promoted up-regulation of LOX-1 expression either in cultured endothelial cells or in the aortas of mice, which was reversed with the administration of olmesartan. Our data indicated that olmesartan may attenuate the impairment of endothelial cell via down-regulation of the increased LOX-1 expression induced by ox-LDL. PMID:22408405

  6. Localized Delivery of Low-Density Lipoprotein Docosahexaenoic Acid Nanoparticles to the Rat Brain using Focused Ultrasound

    PubMed Central

    Mulik, Rohit S.; Bing, Chenchen; Ladouceur-Wodzak, Michelle; Munaweera, Imalka; Chopra, Rajiv; Corbin, Ian R.

    2016-01-01

    Focused ultrasound exposures in the presence of microbubbles can achieve transient, non-invasive, and localized blood-brain barrier (BBB) opening, offering a method for targeted delivery of therapeutic agents into the brain. Low-density lipoprotein (LDL) nanoparticles reconstituted with docosahexaenoic acid (DHA) could have significant therapeutic value in the brain, since DHA is known to be neuroprotective. BBB opening was achieved using pulsed ultrasound exposures in a localized brain region in normal rats, after which LDL nanoparticles containing the fluorescent probe DiR (1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindotricarbocyanine Iodide) or DHA were administered intravenously. Fluorescent imaging of brain tissue from rats administered LDL-DiR demonstrated strong localization of fluorescence signal in the exposed hemisphere. LDL-DHA administration produced 2× more DHA in the exposed region of the brain, with a corresponding increase in Resolvin D1 levels, indicating DHA was incorporated into cells and metabolized. Histological evaluation did not indicate any evidence of increased tissue damage in exposed brain regions compared to normal brain. This work demonstrates that localized delivery of DHA to the brain is possible using systemically-administered LDL nanoparticles combined with pulsed focused ultrasound exposures in the brain. This technology could be used in regions of acute brain injury or as a means to target infiltrating tumor cells in the brain. PMID:26790145

  7. Localized delivery of low-density lipoprotein docosahexaenoic acid nanoparticles to the rat brain using focused ultrasound.

    PubMed

    Mulik, Rohit S; Bing, Chenchen; Ladouceur-Wodzak, Michelle; Munaweera, Imalka; Chopra, Rajiv; Corbin, Ian R

    2016-03-01

    Focused ultrasound exposures in the presence of microbubbles can achieve transient, non-invasive, and localized blood-brain barrier (BBB) opening, offering a method for targeted delivery of therapeutic agents into the brain. Low-density lipoprotein (LDL) nanoparticles reconstituted with docosahexaenoic acid (DHA) could have significant therapeutic value in the brain, since DHA is known to be neuroprotective. BBB opening was achieved using pulsed ultrasound exposures in a localized brain region in normal rats, after which LDL nanoparticles containing the fluorescent probe DiR (1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindotricarbocyanine Iodide) or DHA were administered intravenously. Fluorescent imaging of brain tissue from rats administered LDL-DiR demonstrated strong localization of fluorescence signal in the exposed hemisphere. LDL-DHA administration produced 2 × more DHA in the exposed region of the brain, with a corresponding increase in Resolvin D1 levels, indicating DHA was incorporated into cells and metabolized. Histological evaluation did not indicate any evidence of increased tissue damage in exposed brain regions compared to normal brain. This work demonstrates that localized delivery of DHA to the brain is possible using systemically-administered LDL nanoparticles combined with pulsed focused ultrasound exposures in the brain. This technology could be used in regions of acute brain injury or as a means to target infiltrating tumor cells in the brain. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Toll-Like Receptor 4 Mediates Inflammatory Cytokine Secretion in Smooth Muscle Cells Induced by Oxidized Low-Density Lipoprotein

    PubMed Central

    Cao, Li Juan; Liu, Xin He; Liu, Zhu Hui; Wang, Xiao Qun; Chen, Qiu Jin; Lu, Lin; Shen, Wei Feng; Liu, Yan

    2014-01-01

    Oxidized low-density lipoprotein (oxLDL)-regulated secretion of inflammatory cytokines in smooth muscle cells (SMCs) is regarded as an important step in the progression of atherosclerosis; however, its underlying mechanism remains unclear. This study investigated the role of toll-like receptor 4 (TLR4) in oxLDL-induced expression of inflammatory cytokines in SMCs both in vivo and in vitro. We found that the levels of TLR4, interleukin 1-β (IL1-β), tumor necrosis factor-α (TNFα), monocyte chemoattractant protein 1 (MCP-1) and matrix metalloproteinase-2 (MMP-2) expression were increased in the SMCs of atherosclerotic plaques in patients with femoral artery stenosis. In cultured primary arterial SMCs from wild type mice, oxLDL caused dose- and time-dependent increase in the expression levels of TLR4 and cytokines. These effects were significantly weakened in arterial SMCs derived from TLR4 knockout mice (TLR4−/−). Moreover, the secretion of inflammatory cytokines was blocked by TLR4-specific antibodies in primary SMCs. Ox-LDL induced activation of p38 and NFκB was also inhibited in TLR4−/− primary SMCs or when treated with TLR4-specific antibodies. These results demonstrated that TLR4 is a crucial mediator in oxLDL-induced inflammatory cytokine expression and secretion, and p38 and NFκB activation. PMID:24755612

  9. Berberine as a photosensitizing agent for antitumoral photodynamic therapy: Insights into its association to low density lipoproteins.

    PubMed

    Luiza Andreazza, Nathalia; Vevert-Bizet, Christine; Bourg-Heckly, Geneviève; Sureau, Franck; José Salvador, Marcos; Bonneau, Stephanie

    2016-08-20

    Recent years have seen a growing interest in Berberine, a phytochemical with multispectrum therapeutic activities, as anti-tumoral agent for photodynamic therapy (PDT). In this context, low density lipoproteins (LDL) play a key role in the delivery of the photosensitizer in tumor cells. We correlate the physicochemical parameters of the berberine association to LDL with the influence of LDL-delivery on its accumulation in a glioma cell line and on its photo-induced activity in view of antitumor PDT. Our results evidence an important binding of 400 berberine molecules per LDL. Changes in berberine and apoprotein fluorescence suggest different fixation types, involving various LDL compartments including the vicinity of the apoprotein. The berberine association to LDL does not affect their recognition by the specific B/E receptors, of which over-expression increases the cellular uptake of LDL-preloaded berberine. Fluorescence microscopy evidences the mitochondrial labeling of the glioma model cells, with no significant modification upon LDL-delivery. Moreover, the cellular delivery of berberine by LDL increases its photocytotoxic effects on such cells. So, this research illustrates the potential of berberine as a photosensitizing agent for PDT, in particular due to their behavior towards LDL as plasma vehicles, and gives insights into its mechanisms of cell uptake. Copyright © 2016. Published by Elsevier B.V.

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

    SciTech Connect

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

    1990-07-01

    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 for a monocyte chemotactic protein 1 (MCP-1) that is constitutively produced by the human glioma U-105MG cell line. Antibody that had been prepared against cultured baboon smooth muscle cell chemotactic factor (anti-SMCF) did not inhibit monocyte migration induced by the potent bacterial chemotactic factor f-Met-Leu-Phe. However, anti-SMCF completely inhibited the monocyte chemotactic activity found in the media of U-105MG cells, EC, and SMC before and after exposure to MM-LDL. Moreover, monocyte migration into the subendothelial space of a coculture of EC and SMC that had been exposed to MM-LDL was completely inhibited by anti-SMCF. Anti-SMCF specifically immunoprecipitated 10-kDa and 12.5-kDa proteins from EC. Incorporation of (35S)methionine into the immunoprecipitated proteins paralleled the monocyte chemotactic activity found in the medium of MM-LDL stimulated EC and the levels of MCP-1 mRNA found in the EC. We conclude that SMCF is in fact MCP-1 and MCP-1 is induced by MM-LDL.

  11. Low-density lipoprotein cholesterol level in patients with acute myocardial infarction having percutaneous coronary intervention (the cholesterol paradox).

    PubMed

    Cho, Kyung Hoon; Jeong, Myung Ho; Ahn, Youngkeun; Kim, Young Jo; Chae, Shung Chull; Hong, Taek Jong; Seong, In Whan; Chae, Jei Keon; Kim, Chong Jin; Cho, Myeong Chan; Seung, Ki Bae; Park, Seung Jung

    2010-10-15

    The relation between low-density lipoprotein (LDL) cholesterol levels and clinical outcomes after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) has not been described. A total of 9,571 eligible patients (mean age 62.6 ± 12.5 years, 6,967 men) who underwent PCI with a final diagnosis of AMI from the Korea Acute Myocardial Infarction Registry (KAMIR) were divided into 5 groups according to LDL cholesterol level: < 70, 70 to 99, 100 to 129, 130 to 159, and ≥ 160 mg/dl. Clinical outcomes in hospital and 1 and 12 months after PCI in patients with AMI were examined. Age and co-morbidities decreased as LDL cholesterol increased. Patients with higher LDL cholesterol levels had favorable hemodynamic status and laboratory findings. Lifesaving medications, including lipid-lowering drugs, were underused in patients with lower LDL cholesterol levels. Clinical outcomes in hospital and 1 and 12 months after PCI showed better results as LDL cholesterol increased, except for patients with LDL cholesterol levels ≥ 160 mg/dl. In a Cox proportional-hazards model, LDL cholesterol level was not an independent predictor of mortality at 12 months, after adjusting for clinical characteristics including demographics and biologic data. In conclusion, the cholesterol paradox in patients with AMI is related to confounding by baseline characteristics associated with survival. More intensive treatment including lipid-lowering therapy for AMI in patients with lower LDL cholesterol level may result in better clinical outcomes.

  12. Homocysteine in relation to C-reactive protein and low-density lipoprotein cholesterol in assessment of cardiovascular risk.

    PubMed

    Herrmann, W; Obeid, R; Hübner, U; Jouma, M; Geisel, J

    2004-12-01

    Coronary vascular disease (CVD) is a chronic, multifactorial disease that occurs often in individuals without known risk factors. We investigated the predictive value of homocysteine (Hcy) in relation to C-reactive protein (CRP) and low-density lipoprotein (LDL)-cholesterol in patients with confirmed coronary disease. The study included 87 German and 92 Syrian patients in addition to 87 German and 64 Syrian control individuals. Patients and controls were of comparable age, lifestyles and cultural background. Patients of both ethnic groups had significantly higher concentrations of Hcy and C-reactive protein compared to the controls. The lipids were higher only in Syrian patients compared to the controls. Elevated concentrations of Hcy or that of CRP (>75th percentiles) were associated with increased probability for CVD. In both population groups, the risk increased markedly in subjects who had elevated concentrations of Hcy and CRP or those who had elevated concentrations of Hcy and LDL-cholesterol. The results emphasize that detemination of Hcy may improve the predictive value of C-reactive protein and the LDL-cholesterol. Measurements of these markers are especially important for identification of patients at high risk for CVD.

  13. Effects of a 12-week healthy-life exercise program on oxidized low-density lipoprotein cholesterol and carotid intima-media thickness in obese elderly women

    PubMed Central

    Park, Jong-Hwan; Park, Hyuntae; Lim, Seung-Taek; Park, Jin-Kee

    2015-01-01

    [Purpose] This study examined the effects of a 12-week exercise program on plasma level of oxidized low-density lipoprotein cholesterol in obese elderly women, who are at increased risk of heart disease morbidity. [Subjects and Methods] Twenty participants were assigned into either a control (n = 10) or a supervised exercise program (n = 10) group. The 12-week exercise intervention was performed 3 days per week and involved combined aerobic exercise, resistance exercise, and traditional Korean dance. [Results] Two-factor analysis of variance revealed significant group × time interactions for body mass, diastolic blood pressure, appendicular muscle mass. For high-density lipoprotein cholesterol, oxidized low-density lipoprotein cholesterol, and the ratio of oxidized low-/high-density lipoprotein cholesterol, two-factor analysis of variance revealed significant interactions (group × time), indicating responses differed significantly between the control and exercise groups after 12 weeks. [Conclusion] A 12-week low- to moderate-intensity exercise program appears to be beneficial for obese elderly women by improving risk factors for cardiovascular disease. PMID:26157235

  14. Remnant lipoproteins induced proliferation of human prostate cancer cell, PC-3 but not LNCaP, via low density lipoprotein receptor.

    PubMed

    Sekine, Yoshitaka; Koike, Hidekazu; Nakano, Takamitsu; Nakajima, Katsuyuki; Takahashi, Sadao; Suzuki, Kazuhiro

    2009-07-01

    Hypertriglyceridemia has been shown to be one of the risk factors for prostate cancer. In this study, we investigated the effect of remnant lipoproteins on cell growth in prostate cancer cell lines. Remnant lipoproteins were isolated as remnant like particles (RLP) from human plasma. We used RLP for TG-rich lipoproteins and low density lipoproteins (LDL) for cholesterol-rich lipoproteins respectively and examined the effect of lipoproteins on proliferation of PC-3 and LNCaP cells using MTS assays. Moreover, we studied the effect of RLP and LDL treatment on the regulation of lipoprotein receptors in prostate cancer cells to investigate the relationship between lipoprotein-induced cell proliferation and lipoprotein receptor expression using real-time PCR, Western blotting assays and siRNA. RLP effectively induced PC-3 cell proliferation more than LDL, whereas both RLP and LDL could not induce LNCaP cell proliferation except at a higher concentration of RLP. LDL receptor (LDLr) was expressed in both prostate cancer cells but there was a sharp difference of sterol regulation between two cells. In PC-3 cells, LDL decreased the LDLr expression in some degree, but RLP did not. Meanwhile LDLr expression in LNCaP was easily downregulated by RLP and LDL. Blocking LDLr function significantly inhibited both RLP- and LDL-induced PC-3 cell proliferation. This study demonstrated that RLP-induced PC-3 cell proliferation more than LDL; however, both RLP and LDL hardly induced LNCaP cell proliferation. The differences of proliferation by lipoproteins might be involved in the regulation of LDLr expression.

  15. Low density lipoprotein detection based on antibody immobilized self-assembled monolayer: investigations of kinetic and thermodynamic properties.

    PubMed

    Matharu, Zimple; Bandodkar, Amay Jairaj; Sumana, G; Solanki, Pratima R; Ekanayake, E M I Mala; Kaneto, Keiichi; Gupta, Vinay; Malhotra, B D

    2009-10-29

    Human plasma low density lipoprotein (LDL) immunosensor based on surface plasmon resonance (SPR) and quartz crystal microbalance (QCM) was fabricated by immobilizing antiapolipoprotein B (AAB) onto self-assembled monolayer (SAM) of 4-aminothiophenol (ATP). The AAB/ATP/Au immunosensor can detect LDL up to 0.252 microM (84 mg/dL) and 0.360 microM (120 mg/dL) with QCM and SPR, respectively. The SPR and QCM measurements were further utilized to study the reaction kinetics of the AAB-LDL interaction. The adsorption process involved was explored using Langmuir adsorption isotherm and Freundlich adsorption models. The thermodynamic parameters such as change in Gibb's free energy (DeltaG(ads)), change in enthalpy (DeltaH(ads)), and change in entropy (DeltaS(ads)) determined at 283, 298, and 308 K revealed that the AAB-LDL interaction is endothermic in nature and is governed by entropy. Kinetic, thermodynamic, and sticking probability studies disclosed that desorption of the water molecules from the active sites of AAB and LDL plays a key role in the interaction process and increase in temperature favors binding of LDL with the AAB/ATP/Au immunosensor. Thus, the studies were utilized to unravel the most important subprocess involved in the adsorption of LDL onto AAB-modified ATP/Au surface that may help in the fabrication of LDL immunosensors with better efficiency.

  16. Low density lipoprotein receptor-related protein 1 mediated endocytosis of β1-integrin influences cell adhesion and cell migration.

    PubMed

    Rabiej, Verena K; Pflanzner, Thorsten; Wagner, Timo; Goetze, Kristina; Storck, Steffen E; Eble, Johannes A; Weggen, Sascha; Mueller-Klieser, Wolfgang; Pietrzik, Claus U

    2016-01-01

    The low density lipoprotein receptor-related protein 1 (LRP1) has been shown to interact with β1-integrin and regulate its surface expression. LRP1 knock-out cells exhibit altered cytoskeleton organization and decreased cell migration. Here we demonstrate coupled endocytosis of LRP1 and β1-integrin and the involvement of the intracellular NPxY2 motif of LRP1 in this process. Mouse embryonic fibroblasts harboring a knock in replacement of the NPxY2 motif of LRP1 by a multiple alanine cassette (AAxA) showed elevated surface expression of β1-integrin and decreased β1-integrin internalization rates. As a consequence, cell spreading was altered and adhesion rates were increased in our cell model. Cells formed more focal adhesion complexes, whereby in vitro cell migration rates were decreased. Similar results could be observed in a corresponding mouse model, the C57Bl6 LRP1 NPxYxxL knock in mice, therefore, the biochemistry of cellular adhesion was altered in primary cortical neurons. In vivo cell migration experiments demonstrated a disturbance of neuroblast cell migration along the rostral migratory stream. In summary, our results indicate that LRP1 interacts with β1-integrin mediating integrin internalization and thus correlates with downstream signaling of β1-integrin such as focal adhesion dynamics. Consequently, the disturbance of this interaction resulted in a dysfunction in in vivo and in vitro cell adhesion and cell migration.

  17. Prickly pear (Opuntia sp.) pectin reverses low density lipoprotein receptor suppression induced by a hypercholesterolemic diet in guinea pigs.

    PubMed

    Fernandez, M L; Lin, E C; Trejo, A; McNamara, D J

    1992-12-01

    The effects of prickly pear pectin on plasma LDL metabolism were investigated by feeding guinea pigs either a diet containing 15 g/100 g lard and 0.25 g/100 g cholesterol (LC diet) or the LC diet in which cellulose was partially replaced (2.5 g/100 g) by prickly pear pectin (LC-P diet). The LC-P diet lowered plasma LDL cholesterol concentrations by 33% (P < 0.001). Low density lipoprotein composition was modified by intake of prickly pear pectin; the relative percentages of free and esterified cholesterol were lower and triglycerides were higher in LDL from animals fed the LC-P diet (P < 0.05). Intake of prickly pear pectin did not affect hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity; however, hepatic free and esterified cholesterol concentrations were lowered by 46 and 64%, respectively. Hepatic apolipoprotein B/E receptor expression (Bmax) was 60% higher in animals fed the LC-P diet (P < 0.01). Similar to the in vitro data, receptor-mediated LDL fractional catabolic rates were 190% higher in animals fed the LC-P diet (P < 0.05), whereas apolipoprotein LDL flux rates were not affected. Apolipoprotein LDL pool size and fractional catabolic rates exhibited a significant correlation (r = -0.52, P < 0.01). These data indicate that an increase in apolipoprotein B/E receptor expression is a major metabolic response by which intake of prickly pear pectin decreases plasma LDL concentrations.

  18. Differential effects of grape ( Vitis vinifera ) skin polyphenolics on human platelet aggregation and low-density lipoprotein oxidation.

    PubMed

    Shanmuganayagam, Dhanansayan; Beahm, Mark R; Kuhns, Melissa A; Krueger, Christian G; Reed, Jess D; Folts, John D

    2012-06-13

    Antioxidant and antiplatelet properties of grape products are thought to be responsible for observed antiatherosclerotic effects. Diverse classes of phenolics are derived from the seed and skin (GSK) of grapes. The relative contributions of the classes of phenolics to observed properties of grape products are unknown. In this paper, GSK fractions were used to examine effects on platelet aggregation, low-density lipoprotein (LDL) oxidation in vitro, and relative binding of phenolics to LDL. GSK was separated into six fractions (fractions 1-6), and primary phenolics were characterized using high-performance liquid chromatography and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Fractions 4, 5, and 6, enriched in polygalloyl polyflavan-3-ols (PGPFs) with 3-6, 4-8, and 6-15 degrees of polymerization, respectively, inhibited platelet aggregation. Fractions 1-3, containing various amounts of oligosaccharides, hydroxycinnamic acids, anthocyanins, flavanols, and low molecular weight PGPFs, significantly increased platelet aggregation. Fractions 4-6 were most effective in binding LDL and inhibiting LDL oxidation. Fractions 5 and 6 exhibited the greatest inhibition of platelet aggregation and LDL oxidation, suggesting that polymeric PGPFs are responsible for the beneficial effects of grape products. Conversely, phenolics in fractions 1-3 may reduce the net biological potency of the grape products and have undesirable effects on cardiovascular disease risk factors.

  19. Effects of retinoids on differentiation, lipid metabolism, epidermal growth factor, and low-density lipoprotein binding in squamous carcinoma cells

    SciTech Connect

    Ponec, M.; Weerheim, A. ); Havekes, L. ); Boonstra, J. )

    1987-08-01

    The relationship among keratinocyte differentiation capacity, lipid synthesis, low-density lipoprotein (LDL) metabolism, plasma membrane composition, and epidermal growth factor (EGF) binding has been studied in SCC-12F2 cells. The differentiation capacity of the cells, i.e., ionophore-induced cornified envelope formation, was inhibited by various retinoids and stimulated by hydrocortisone. Retinoids that caused a significant reduction of cornified envelope formation, i.e., retinoic acid and 13-cis-retinoic acid, caused only minor changes in lipid synthesis and plasma membrane composition. Arotinoid ethylsulfone, having a minor effect on cornified envelope formation, caused a drastic inhibition of cholesterol synthesis resulting in changes in the plasma membrane composition. Hydrocortisone stimulated cornified envelope formation but had only minor effects on lipid synthesis and plasma membrane composition. Of all retinoids tested, only arotinoid ethylsulfone caused a drastic increase in EGF binding, while hydrocortisone had no effect. These results clearly demonstrate that the plasma membrane composition is not related to keratinocyte differentiation capacity, but most likely does determine EGF binding. Furthermore, EGF binding does not determine keratinocyte differentiation capacity.

  20. Molecular Imaging of Native Low-Density Lipoprotein by Near-Infrared Fluorescent Angioscopy in Human Coronary Plaques.

    PubMed

    Uchida, Yasumi; Yoshida, Tomoe; Shimoyama, Ei; Uchida, Yasuto

    2016-03-01

    Low-density lipoprotein (LDL) is an important risk factor for coronary artery disease, but its localization within the human coronary arterial wall is poorly understood. Imaging of LDL in 30 coronary arteries excised from 15 subjects who underwent autopsy was performed using near-infrared fluorescent angioscopy system and using indocyanine green dye as a biomarker of LDL. The percentage incidence of LDL in 28 normal segments, 24 white plaques (early stage of plaque growth), and 21 yellow plaques (mature stage of plaque) classified by conventional angioscopy, was 14.2, 79.1 (p <0.01 vs normal segments and p <0.05 vs yellow plaques), and 28.5, respectively. Coronary near-infrared fluorescent angioscopy showed similar results in 7 patients in vivo. Our results suggested that LDL begins to deposit in the human coronary arterial wall in the early stage of atherosclerosis, increasingly deposits with plaque growth and decreases in the mature stage; and therefore, molecular therapy targeting LDL should be started before plaque maturation.

  1. Protective effect of rosuvastatin treatment by regulating oxidized low-density lipoprotein expression in a rat model of liver fibrosis.

    PubMed

    Yu, Shuiping; Zhou, Xueling; Hou, Bingzong; Tang, Bo; Li, Jian; Zhang, Baimeng

    2016-09-01

    The present study aimed to evaluate the protective effect of rosuvastatin treatment on the mechanism of oxidized low-density lipoprotein (Ox-LDL) in rats with liver fibrosis. In total, 72 male Sprague-Dawley rats were divided into 3 groups: 24 in the control group (A), 24 in the obstructive jaundice models group (B) and 24 in the rosuvastatin group (C). Each group was further divided into four subgroups for assessment at different time-points. The obstructive jaundice models were established and rosuvastatin was administered by gavage. Liver fibrosis indicators, Ox-LDL, malonaldehyde (MDA) and superoxide dismutase (SOD), were measured and liver pathological changes were observed at weeks 1, 2, 3 and 4 after model induction. In groups B and C, the rat models were successfully established, and there were significant changes in the expression of Ox-LDL and the three liver fibrosis indicators when compared to group A (P<0.01). However, the expression of Ox-LDL and the three liver fibrosis indicators in group C were decreased compared with group B (P<0.05), while SOD increased (P<0.05) and MDA decreased (P<0.05). The three liver fibrosis indicators were different in comparison to group B (P<0.05). Thus, there appeared to be an association between the expression of Ox-LDL and liver fibrosis. Treatment with rosuvastatin could regulate the expression of Ox-LDL and improve liver fibrosis in rat models with obstructive jaundice.

  2. Effect of curcumin on down-expression of thrombospondin-4 induced by oxidized low-density lipoprotein in mouse macrophages.

    PubMed

    Zhou, Zhong-yun; Chen, Yi-qing; Wang, Fei-yan; Tian, Nan; Fan, Chun-lei

    2014-01-01

    This study was designed to investigate the effect of curcumin on the expression of thrombospondin-4 (THBS-4) in mouse macrophages treated with oxidized low-density lipoprotein (oxLDL). The mouse macrophage cell line ANA-1 was treated with oxLDL. Cell viability was measured by MTT assay. ANA-1 cells were divided into five groups: control group, model group, 5 μM curcumin group, 15 μM curcumin group and 25 μM curcumin group. The gene and protein expression levels of THBS-4 in each group were determined by real-time quantitative polymerase chain reaction (PCR) and western blotting, respectively. MTT assay showed that curcumin concentrations up to 25 μM and oxLDL concentrations up to 20 μg/ml had no significant cytotoxic effects on macrophages at 24 h. Real-time quantitative PCR revealed that THBS-4 mRNA expression was markedly reduced by stimulation with oxLDL, but subsequently significantly increased by treatment with curcumin. Western blotting confirmed that curcumin (5, 15, and 25 μM) significantly prevented the decrease in THBS-4 expression induced by oxLDL (20 μg/ml) in macrophages. Curcumin prevents the decrease in THBS-4 expression induced by oxLDL, which may represent one of the anti-atherosclerotic mechanisms of curcumin.

  3. Mode-of-action evaluation for the effect of trans fatty acids on low-density lipoprotein cholesterol.

    PubMed

    Reichard, John F; Haber, Lynne T

    2016-12-01

    The purpose of this work is to systematically consider the data relating to the mode of action (MOA) for the effects of industrially produced trans fatty acid (iTFA) on plasma low-density lipoprotein (LDL) levels. The hypothesized MOA is composed of two key events: increased LDL production and decreased LDL clearance. A substantial database supports this MOA, although the key events are likely to be interdependent, rather than sequential. Both key events are functions of nonlinear biological processes including rate-limited clearance, receptor-mediated transcription, and both positive and negative feedback regulation. Each key event was evaluated based on weight-of-evidence analysis and for human relevance. We conclude that the data are inadequate for a detailed dose-response analysis in the context of the evolved Bradford Hill considerations; however, the weight of evidence is strong and the overall shape of the dose-response curves for markers of the key events and the key determinants of those relationships is well understood in many cases and is nonlinear. Feedback controls are responsible for maintaining homeostasis of cholesterol and triglyceride levels and underlie both of the key events, resulting in a less-than-linear or thresholded relationship between TFA and LDL-C. The inconsistencies and gaps in the database are discussed. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  4. Association of Plasma Adiponectin and Oxidized Low-Density Lipoprotein with Carotid Intima-Media Thickness in Diabetic Nephropathy

    PubMed Central

    Georgoulidou, Anastasia; Roumeliotis, Athanasios; Roumeliotis, Stefanos; Giannakopoulou, Efstathia; Papanas, Nikolaos; Passadakis, Ploumis; Manolopoulos, Vangelis G.; Vargemezis, Vassilis

    2015-01-01

    Aims. We sought to determine the association between levels of adiponectin and oxidized low-density lipoprotein (ox-LDL) in patients with diabetic nephropathy as well as their effect on carotid intima-media thickness (cIMT). Methods. Adiponectin and ox-LDL were determined in 25 diabetic patients without nephropathy and 94 patients at different stages of diabetic nephropathy including subjects on hemodialysis. cIMT was measured using real-time B-mode ultrasonography. Results. Plasma adiponectin levels increased significantly with severity of diabetic nephropathy (P = 0.002), on the contrary to ox-LDL which decreased with disease severity (P < 0.001). cIMT was significantly higher at late stages of diabetic nephropathy compared with early stages (P = 0.022). Adiponectin was a significant negative predictor of ox-LDL levels (β = −5.45, P = 0.023), independently of confounding factors. There was no significant correlation between cIMT and adiponectin or ox-LDL either in the total sample population or according to disease staging. Cluster analysis showed that patients with the highest cIMT values, highest levels of adiponectin, and lowest levels of ox-LDL were included in one cluster and all assigned to stage 5 of diabetic nephropathy. Conclusions. There was no significant association between adiponectin or ox-LDL and cIMT and, therefore, other factors affecting this surrogate marker of cardiovascular disease in diabetic nephropathy should be sought. PMID:26064982

  5. Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia.

    PubMed Central

    Bilheimer, D W; Goldstein, J L; Grundy, S M; Brown, M S

    1975-01-01

    The turnover of 125I-labeled low density lipoprotein (LDL) and the total body balance of cholestrol were studied in a 6-yr-old girl with the homozygous form of familial hypercholesterolemia (FH) before and after the surgical creation of an end-to-side portacaval shunt. The results were compared with those of similar studies simultaneously performed in untreated patients with the heterozygous form of FH and with the results of earlier studies performed on normolipidemic subjects. Before shunt surgery, the rate of synthesis of LDL in the FH homozygote (mg/kg per day) was fourfold higher than in normolipidemic subjects and twofold higher than in her heterozygous mother. The fractional catabolic rate for LDL in the homozygote was decreased to 33% of normal control values. The rate of cholesterol synthesis, estimated by chemical sterol balance, was higher in the FH homozygote than in two FH heterozygotes of similar age studied simultaneously. When considered in relation to the markedly elevated level of plasma cholesterol, the observed rate of cholesterol synthesis in the FH homozygote was inappropriately elevated. Bile acid production was normal in all three children. 5 mo after shunt surgery, the rate of LDL synthesis in the homozygote had declined by 48% as compared with the preoperative value, and this caused a 39% drop in the plasma LDL cholesterol level despite a 17% reduction in the fractional catabolic rate of the lipoprotein. The rate of cholesterol synthesis fell by 62% as compared with the preoperative value. The findings of an inappropriately elevated rate of production of both cholesterol and LDL as well as a reduced fractional catabolic rate for the lipoprotein in the untreated FH homozygote are consistent with results of studies in cultured fibroblasts indicating that the primary genetic defect in FH involves a deficiency in a cell-surface receptor for LDL that regulates both cholesterol synthesis and LDL degradation. Although the mechanism for the

  6. Joint effect of high-density lipoprotein cholesterol and low-density lipoprotein cholesterol on the risk of coronary heart disease.

    PubMed

    Hu, Gang; Cui, Yadong; Jousilahti, Pekka; Sundvall, Jouko; Girman, Cynthia J; Antikainen, Riitta; Laatikainen, Tiina; Tuomilehto, Jaakko

    2013-02-01

    To evaluate the single and joint associations of serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol with coronary heart disease (CHD) risk. Study cohorts included 21,375 Finnish participants who were 25-74 years of age and free of CHD and stroke at baseline. During a median follow-up period of 10.8 years, 437 participants developed CHD. The sex- and multivariable-adjusted hazard ratios (HRs) of CHD at different levels of HDL cholesterol [<40 (reference), 40-49, 50-59, 60-69, and ≥ 70 mg/dL] were 1.00, 1.00, 0.74, 0.58, and 0.69 (p (trend) = 0.006), respectively. The sex- and multivariable-adjusted HRs of CHD at different levels of LDL cholesterol [<100 (reference), 100-129, 130-159, and ≥ 160 mg/dL] were 1.00, 1.25, 1.92, and 2.65 (p (trend) < 0.001), respectively. In joint analyses, a decreased trend in the incidence rate of CHD with an increasing HDL cholesterol level was consistent in people with any level of LDL cholesterol. Likewise, an increasing trend in incidence of CHD with an increase in the LDL cholesterol level was consistent in subjects with any level of HDL cholesterol. These results suggest an inverse association between HDL cholesterol and CHD risk and a direct association between LDL cholesterol and CHD risk, independent of other risk factors. The protective effect of HDL cholesterol on CHD risk is observed at all levels of LDL cholesterol.

  7. Thermal transitions in human very-low-density lipoprotein: fusion, rupture, and dissociation of HDL-like particles.

    PubMed

    Guha, Madhumita; England, Cheryl; Herscovitz, Haya; Gursky, Olga

    2007-05-22

    Very-low-density lipoproteins (VLDL) are metabolic precursors of low-density lipoproteins (LDL) and a risk factor for atherosclerosis. Human VLDL are heterogeneous complexes containing a triacylglycerol-rich apolar lipid core and polar surface composed of phospholipids, a nonexchangeable apolipoprotein B, and exchangeable apolipoproteins E and Cs. We report the first stability study of VLDL. Circular dichroism and turbidity data reveal an irreversible heat-induced VLDL transition that involves formation of larger particles and repacking of apolar lipids but no global protein unfolding. Heating rate effect on the melting temperature indicates a kinetically controlled reaction with high activation energy, Ea. Arrhenius analysis of the turbidity data reveals two kinetic phases with Ea = 53 +/- 7 kcal/mol that correspond to distinct morphological transitions observed by electron microscopy. One transition involves VLDL fusion, partial rupture, and dissociation of small spherical particles (d = 7-15 nm), and another involves complete lipoprotein disintegration and lipid coalescence into droplets accompanied by dissociation of apolipoprotein B. The small particles, which are unique to VLDL denaturation, are comparable in size and density to high-density lipoproteins (HDL); they have an apolar lipid core and polar surface composed of exchangeable apolipoproteins (E and possibly Cs) and phospholipids. We conclude that, similar to HDL and LDL, VLDL are stabilized by kinetic barriers that prevent particle fusion and rupture and decelerate spontaneous interconversion among lipoprotein classes and subclasses. In addition to fusion, VLDL disruption involves transient formation of HDL-like particles that may mimic protein exchange among VLDL and HDL pools in plasma.

  8. Serum amyloid A stimulates macrophage foam cell formation via lectin-like oxidized low-density lipoprotein receptor 1 upregulation

    SciTech Connect

    Lee, Ha Young; Kim, Sang Doo; Baek, Suk-Hwan; Choi, Joon Hyuk; Cho, Kyung-Hyun; Zabel, Brian A.; Bae, Yoe-Sik

    2013-03-29

    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-κB 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-κB (NF-κB). 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.

  9. [Study on the selective removal of plasma low-density lipoprotein and fibrinogen by degraded guar sulfate].

    PubMed

    Zhu, Ye; Fang, Bo; Huang, Li; Guan, Chen; Yang, Guang

    2008-10-01

    Degraded guar was prepared by acid with guar as the main material, which was then brought into reaction with chlorosulfonic acid under proper conditions, the sulfonated degraded guar was obtained successfully. The effects of sulfonation conditions on the SO4(2-) content were investigated, and the proper reaction conditions were determined. The results of infrared spectrometry showed that this sulfated derivative is a novel heparin-like polysaccharide. At the same time, the selective removal of low density lipoprotein (LDL) and fibrinogen (Fib) by degraded guar gum sulfate was studied. The experimental results showed that degraded guar gum sulfate is a novel LDL/ Fib purifying agent. When pH= 5.15 and the initial concentration of the degraded guar gum sulfate is 2500 mg/L, the reduction percentages were about 60%-66% for total cholesterol, about 76%-89% for LDL and very low-density lipoproteins (VLDL), and almost 100% for fibrinogen. There were no significant changes regarding the level of high-density lipoproteins and total proteins.

  10. Hepatitis C virus G1b infection decreases the number of small low-density lipoprotein particles.

    PubMed

    Kinoshita, Chika; Nagano, Tomohisa; Seki, Nobuyoshi; Tomita, Yoichi; Sugita, Tomonori; Aida, Yuta; Itagaki, Munenori; Satoh, Kenichi; Sutoh, Satoshi; Abe, Hiroshi; Tsubota, Akihito; Aizawa, Yoshio

    2016-08-07

    To investigate how hepatitis C virus (HCV) G1b infection influences the particle number of lipoproteins. The numbers of lipoprotein particles in fasting sera from 173 Japanese subjects, 82 with active HCV G1b infection (active HCV group) and 91 with cleared HCV infection (SVR group), were examined. Serum lipoprotein was fractionated by high-performance liquid chromatography into twenty fractions. The cholesterol and triglyceride concentrations in each fraction were measured using LipoSEARCH. The number of lipoprotein particles in each fraction was calculated using a newly developed algorithm, and the relationship between chronic HCV G1b infection and the lipoprotein particle number was determined by multiple linear regression analysis. The median number of low-density lipoprotein (LDL) particles was significantly lower in the active