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PubMed1997

Copper-catalyzed oxidation mediates PAF formation in human LDL subspecies. Protective role of PAF:acetylhydrolase in dense LDL.

Free radical-mediated oxidation of cholesterol-rich LDL plays a key role in atherogenesis and involves the formation of oxidized phospholipids with proinflammatory biological activity. We evaluated the production of platelet-activating factor (PAF), a potent inflammatory mediator, in human LDL subspecies on copper-initiated oxidation (4 mumol/L CuCl2, 80 micrograms/mL for hours at 37 degrees C). PAF formation was determined by biological assay of HPLC-purified lipid extracts of copper-oxidized lipoproteins; chemical identity was confirmed by gas chromatographic and mass spectrometric analyses. PAF, characterized as the C16:0 molecular species, was preferentially produced in intermediate LDL (d = 1.029 to 1.039 g/mL) (8.6 +/- 5.7 pmol PAF/3 h per mg LDL protein) and light LDL (d = 1.019 to 1.029 g/mL), but was absent from dense LDL particles (d = 1.050 to 1.063 g/mL). As PAF:acetylhydrolase inactivates PAF and oxidized forms of phosphatidylcholine, we evaluated the relationship of lipoprotein-associated PAF:acetylhydrolase to PAF formation. We confirmed that PAF:acetylhydrolase activity was elevated in native, dense LDL (41.5 +/- 9.5 nmol/min per mg protein) but low in LDL subspecies of light and intermediate density (d 1.020 to 1.039 g/mL) (3.5 +/- 1.6 nmol/min per mg protein) [Tselepis et al, Arterioscler Thromb Vasc Biol. 1995;15:1764-1773]. On copper-mediated oxidation for 3 hours at 37 degrees C, dense LDL particles conserved 20 +/- 14% of their initial enzymatic activity; in contrast, PAF:acetylhydrolase activity was abolished in light and intermediate LDL subspecies. Clearly, the elevated PAF:acetylhydrolase activity of dense LDL efficiently diminishes the potential inflammatory role of endogenously formed PAF; nonetheless, formation of proatherogenic lysophospholipids results. In contrast, LDL particles of the light and intermediate subclasses can accumulate PAF on oxidative modification.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1999

Influence of low density lipoprotein (LDL) subfraction profile and LDL oxidation on endothelium-dependent and independent vasodilation in patients with type 2 diabetes.

Recent studies have suggested that hypercholesterolemia is associated with endothelial dysfunction. In patients with type 2 diabetes mellitus, dyslipidemia is mainly characterized by hypertriglyceridemia, low high density lipoprotein, and a preponderance of small dense low density lipoprotein (LDL) particles. We have examined the relationships among LDL subfractions, the susceptibility of LDL to oxidation in vitro, and endothelial function in type 2 diabetes mellitus. LDL subfractions were measured by density gradient ultracentrifugation. The susceptibility of LDL to oxidation was determined by measuring the kinetics of conjugated dienes formation during copper-mediated oxidation of LDL. Endothelium-dependent and independent vasodilation of the brachial artery were assessed by high resolution vascular ultrasound. Diabetic patients had a higher concentration of small dense LDL-III than matched controls (P < 0.01). The lag phase of conjugated dienes formation was shorter in the diabetic patients (P < 0.05), and the rate of LDL oxidation was faster (P < 0.05). Both endothelium-dependent (P < 0.01) and independent dilation of the brachial artery (P < 0.01) were impaired in the diabetic patients. On multivariate analysis, the rate of oxidation and LDL-III concentration accounted for 12% and 6%, respectively, of the variation in endothelium-dependent vasodilation (adjusted r2 = 0.18; P < 0.05), whereas LDL-III concentration and the maximum amount of conjugated dienes formed accounted for 27% and 5%, respectively, of the variation in endothelium-independent vasodilation (adjusted r2 = 0.32; P < 0.01) in the diabetic patients. In conclusion, endothelial and smooth muscle cell dysfunction in type 2 diabetes were related to abnormalities in LDL subfractions and in LDL oxidation.

Adult↗

PubMed1989

Low-density lipoprotein (LDL) distribution shown by 99mtechnetium-LDL imaging in patients with myeloproliferative diseases.

STUDY OBJECTIVE: To image and identify by noninvasive methods the sites of low-density lipoprotein (LDL) catabolism in patients with myeloproliferative disease in whom chronic hypocholesterolemia was previously reported. STUDY DESIGN: The 99mTechnetium-LDL (Tc-LDL) distribution in patients with myeloproliferative diseases was compared with that in normal subjects. The Tc-LDL distribution was also compared with the distribution and organ uptake of a macrophage-seeking radiotracer. 99mTc-sulfur colloid (Tc-SC). SETTING: Major metropolitan referral center and institutional practice. PATIENTS: Three normal subjects, two patients with polycythemia vera, two with post polycythemia myeloid metaplasia, and one with agnogenic myeloid metaplasia. The patients were being managed with hydroxyurea or phlebotomy. INTERVENTION: Ten mCi of Tc-LDL (homologous) was injected intravenously. MEASUREMENTS AND MAIN RESULTS: Gamma camera images of Tc-LDL biodistribution and organ uptake were obtained 4 hours after injection of the tracer. In normal subjects, the Tc-LDL was predominantly taken up by the liver, with relative nonvisualization of spleen and central or peripheral marrow. Patients with myeloproliferative disease showed marked splenic uptake of Tc-LDL. Peripheral bone marrow uptake extended to the lower tibia in two patients with post-polycythemia myeloid metaplasia. Splenic and bone marrow uptake paralleled that of Tc-SC. Hypercellularity of central and peripheral marrow at the sites of Tc-LDL uptake was confirmed by biopsy specimens. The Tc-LDL uptake, however, was not correlated with collagen fibrosis. CONCLUSIONS: These results indicate that spleen and bone marrow are sites of LDL catabolism in patients with myeloproliferative disease and suggest the role of macrophages in the hypocholesterolemia and accelerated LDL catabolism of myeloproliferative disease.

Adult↗

PubMed2000

Virgin olive oil phenolic compounds: binding to human low density lipoprotein (LDL) and effect on LDL oxidation.

Oxidation of low density lipoproteins (LDL) appears to occur predominantly in arterial intima in microdomains sequestered from antioxidants of plasma. Therefore phenolic compounds which are able to bind LDL are good drug candidates for the effective prevention of lipid peroxidation and atherosclerotic processes. Plasma from healthy volunteers on nonsupplemented diets was incubated with virgin olive oil phenolic extracts (0-200 mg/l, caffeic acid equivalents). Phenolic compounds in LDL were measured by high-performance liquid chromatography-diode array detection (HPLC-DAD). Copper-mediated LDL oxidation was performed, and conjugated dienes formation was monitored. After plasma preincubation with olive oil phenolic compounds (OOPC), an increased OOPC-concentration dependent was observed in the total phenolic content of LDL (p < 0.001, ANOVA) as well as in the lag time before conjugated diene formation (p < 0.001, ANOVA). Rutin and four phenolics with flavonoid-like spectra were found to be bound to the LDL control. These phenolics, together with tyrosol which was not present in the LDL control, significantly increased in LDL (p < 0.05) after plasma incubation with OOPC. These results show the ability of tyrosol to bind LDL in vitro and the capacity of virgin olive oil phenolics to protect other phenolic compounds previously bound to LDL. These results provide further evidence that phenolic compounds bound to LDL are likely to protect LDL from oxidation.

Analysis of Variance↗

PubMed1989

Stoichiometric binding of low density lipoprotein (LDL) and monoclonal antibodies to LDL receptors in a solid phase assay.

The current paper describes a solid phase ligand binding assay for the low density lipoprotein (LDL) receptor that takes advantage of the domain structure of the protein. An antibody directed against one domain, e.g. the cytoplasmic tail, is adsorbed to a microtiter well. A detergent solution containing the LDL receptor is added, and the receptor is allowed to bind to the antibody. The wells are then washed, and one of the following radioiodinated ligands is added: 125I-LDL or an 125I-labeled monoclonal antibody directed against a different domain than the antibody adsorbed to the well. Under these conditions, the human LDL receptor shows high affinity for 125I-LDL and for 125I-IgG-HL1, a monoclonal antipeptide antibody directed against a 10-amino-acid "linker" between repeats 4 and 5 in the ligand binding domain. The binding affinity is the same at 4 degrees C and 37 degrees C. The binding of 125I-LDL and 125I-IgG-HL1 occurs with 1:1 molar stoichiometry, suggesting that the human LDL receptor binds 1 mol of LDL per mol of receptor. The acid-dependent dissociation of 125I-LDL and 125I-labeled monoclonal antibody from LDL receptors that is observed in intact cells was also shown to occur in the solid phase binding assay. We used the solid phase assay to demonstrate the secretion of LDL receptors from monkey cells that have been transfected with a cDNA encoding a truncated form of the human receptor that lacks the membrane-spanning domain. This assay may be useful in measuring the relative amounts of the intact LDL receptor in tissue extracts and the secreted receptor in transfected cells.

Animals↗

PubMed1994

Human plasma LDL cryopreserved with sucrose maintains in vivo kinetics indistinguishable from freshly isolated human LDL in cynomolgus monkeys.

We previously reported that freeze-thawing of LDL causes marked alterations in its structure and in vitro biological behavior, and that such changes can be completely abolished by the addition of sucrose to the LDL solution prior to freezing. (Rumsey, S. C. et al., J. Lipid Res. 1992. 33: 1551-1561). We now questioned whether the cryopreservative action of sucrose would be equally effective in maintaining the in vivo metabolic characteristics of LDL. Two dual-label LDL turnover studies were performed in cynomolgus monkeys (n = 8) comparing freshly isolated human LDL with human LDL that was frozen in sucrose (10% w/v) for a short (20 h) or long period (6 months). The same sucrose-cryopreserved LDL was used for both the short- and long-term studies; different fresh LDL preparations were used in each study. Absorption spectrophotometry, gel filtration, and electron microscopy of LDL samples frozen with sucrose showed no evidence of physical alterations or aggregation, and there was no evidence of very rapid clearance of cryopreserved LDL from monkey plasma after injection. Fractional catabolic rates (FCR) of fresh and frozen LDL were very similar in either the short-term or long-term experiments: 2.09 +/- 0.86 versus 2.16 +/- 0.88, short-term and 3.03 +/- 2.28 versus 3.08 +/- 2.29, long-term (pools per day; mean +/- SD). The difference between FCR of fresh and frozen LDL for each animal averaged -0.076 +/- 0.074 and 0.01 +/- 0.22 (mean +/- SD), for short-term and long-term freezing, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2001

Oxidized LDL modulates Bax/Bcl-2 through the lectinlike Ox-LDL receptor-1 in vascular smooth muscle cells.

Oxidized low density lipoprotein (Ox-LDL) induces apoptosis in vascular smooth muscle cells (VSMCs), which may increase atherosclerotic plaque instability. In this study, we examined the molecular mechanisms causing the Ox-LDL-induced apoptosis in VSMCs, especially focusing on the involvement of Bax/Bcl-2 and the lectinlike Ox-LDL receptor-1 (LOX-1). In cultured bovine aortic smooth muscle cells (BASMCs), Ox-LDL at high concentrations (>60 microg/mL) induced cell death as demonstrated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. DNA fragmentation was increased in BASMCs treated with high concentrations of Ox-LDL, indicating that the Ox-LDL-induced cell death in VSMCs was apoptosis. Ox-LDL upregulated LOX-1 expression through phosphorylation of extracellular signal-regulated kinase in BASMCs, and a neutralizing anti-LOX-1 monoclonal antibody, which can block LOX-1-mediated cellular uptake of Ox-LDL, prevented the Ox-LDL-induced apoptosis in BASMCs. This antibody also suppressed the increase in the Bax to Bcl-2 ratio induced by Ox-LDL in BASMCs. Furthermore, LOX-1 expression was well colocalized with Bax expression in the rupture-prone shoulder areas of human atherosclerotic plaques in vivo. LOX-1 may play an important role in Ox-LDL-induced apoptosis in VSMCs by modulating the Bax to Bcl-2 ratio. These molecular mechanisms may be involved in destabilization and rupture of atherosclerotic plaques.

Animals↗

PubMed1998

Identification of the principal proteoglycan-binding site in LDL. A single-point mutation in apo-B100 severely affects proteoglycan interaction without affecting LDL receptor binding.

The subendothelial retention of LDLs through their interaction with proteoglycans has been proposed to be a key process in the pathogenesis of atherosclerosis. In vitro studies have identified eight clusters of basic amino acids in delipidated apo-B100, the protein moiety of LDL, that bind the negatively charged proteoglycans. To determine which of these sites is functional on the surface of LDL particles, we analyzed the proteoglycan-binding activity of recombinant human LDL isolated from transgenic mice. Substitution of neutral amino acids for the basic amino acids residues in site B (residues 3359-3369) abolished both the receptor-binding and the proteoglycan-binding activities of the recombinant LDL. Chemical modification of the remaining basic residues caused only a marginal further reduction in proteoglycan binding, indicating that site B is the primary proteoglycan-binding site of LDL. Although site B was essential for normal receptor-binding and proteoglycan-binding activities, these activities could be separated in recombinant LDL containing single-point mutation. Recombinant LDL with a K3363E mutation, in which a glutamic acid had been inserted into the basic cluster RKR in site B, had normal receptor binding but interacted defectively with proteoglycans; in contrast, another mutant LDL, R3500Q, displayed defective receptor binding but interacted normally with proteoglycans. LDL with normal receptor-binding activity but with severely impaired proteoglycan binding will be a unique resource for analyzing the importance of LDL- proteoglycan interaction in atherogenesis. If the subendothelial retention of LDL by proteoglycans is the initial event in early atherosclerosis, then LDL with defective proteoglycan binding may have little or no atherogenic potential.

Amino Acid Substitution↗

PubMed1989

Regulation of low density lipoprotein apoprotein B metabolism by lovastatin and cholestyramine in miniature pigs: effects on LDL composition and synthesis of LDL subfractions.

A major factor in the regulation of low density lipoprotein (LDL) apoprotein B (apo B) concentrations in miniature pigs is the direct synthesis of LDL apo B. LDL apo B derived from plasma very low density lipoproteins (VLDL) accounts for only 20% to 30% of total LDL synthesis. Treatment with lovastatin and cholestyramine can inhibit the direct synthesis pathway in this species, thereby lowering LDL apo B concentrations. The present study was carried out to determine if lovastatin alone was as effective as in combination with cholestyramine. The possibility that the direct synthesis pathway was confined to a specific subclass of LDL and the effect of lovastatin and cholestyramine on the metabolism of LDL subfractions were also investigated. Homologous 125I-VLDL and 131I-LDL were injected into miniature pigs during a control period and again following 18 days of treatment with lovastatin (1.2 mg/kg/d, n = 4) or in combination with cholestyramine (1.0 g/kg/d, n = 4). Kinetic analysis of apo B specific activity curves following lovastatin treatment indicated that LDL apo B pool size was decreased by 25% (P less than .025), which was due entirely to a 70% (P less than .025) decrease in the direct synthesis of LDL apo B, since VLDL-derived apo B, and LDL fractional catabolic rate (FCR) were not affected. Parameters of VLDL apo B metabolism were not affected. Lovastatin in combination with cholestyramine was more effective than lovastatin alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Recognition of solubilized apoproteins from delipidated, oxidized low density lipoprotein (LDL) by the acetyl-LDL receptor.

Macrophages express a specific receptor that recognizes acetylated low density lipoprotein (LDL) and certain other chemically modified forms of LDL but not native LDL. LDL oxidatively modified either by incubation with endothelial cells in Ham's F-10 medium or by incubation with 5 microM copper(II) ion in the absence of cells is recognized by this same receptor. This oxidative modification, whether cell-induced or copper-catalyzed, is accompanied by many changes in the physical and chemical properties of LDL, including an increase in density, conversion of phosphatidylcholine to lysophosphatidylcholine, generation of lipid peroxides, and degradation of apolipoprotein B-100. Which changes are essential for eliciting the recognition by the receptor is not known. In the present paper it is shown that fragments of the degraded apolipoprotein from delipidated, oxidized LDL can be almost quantitatively resolubilized using n-octyl beta-D-glucopyranoside. These 125I-labeled, solubilized apoproteins were degraded rapidly by mouse peritoneal macrophages, and that degradation was competitively inhibited by unlabeled acetyl-LDL and endothelial cell-modified LDL but not by native LDL. These results show that the acetyl-LDL receptor recognizes an epitope on the apoprotein moiety, either newly generated or exposed as a result of oxidative modification, rather than some oxidized lipid moiety. Further, the results suggest that the lipids of oxidatively modified LDL do not play an obligatory role in determining the conformation of that epitope.

Animals↗

PubMed2001

Effects of plant stanol esters on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase mRNA expression in mononuclear blood cells of healthy men and women.

Functional foods enriched with plant stanols lower atherogenic LDL cholesterol concentrations. This effect is caused at least partly by a decreased intestinal cholesterol absorption. It has been suggested that LDL production is reduced after plant stanol consumption, but it is unknown whether LDL receptor expression is affected and contributes to the LDL-lowering effect of plant stanols. Markers for endogenous cholesterol synthesis (lathosterol) increase, but it is not known how this higher cholesterol synthesis is regulated at the molecular level. In a double-blind placebo controlled trial, we have found that compared with the control group (N=15), daily consumption of 3.8-4.0 g plant stanol esters (N=29) for 8 weeks increased LDL receptor mRNA levels in human mononuclear blood cells by 43% (P=0.003). LDL receptor protein concentrations on the surface of monocytes and T lymphocytes increased by 37% (P=0.003) and 25% (P=0.013), suggesting an increased translation. This increased protein expression appeared to be functional, since changes in serum LDL cholesterol correlated negatively with changes in LDL receptor mRNA levels (r=-0.361; P=0.015) and changes in LDL receptor protein expression in monocytes (r=-0.440; P<0.001) and T lymphocytes (r=-0.307; P=0.018). Based on these results, we suggest that the higher LDL receptor expression contributed to a lowered LDL formation along the apoB cascade. Whole body cholesterol synthesis increased, as indicated by the rise in serum cholesterol-standardized lathosterol concentrations, but the 34% increased HMG-CoA reductase mRNA concentrations did not reach statistical significance. Nor did it correlate significantly with changes in serum cholesterol-standardized lathosterol concentrations. This suggests that HMG-CoA reductase may be only partly regulated at a transcriptional level.

Cholesterol↗

PubMed1999

Comparison of the LDL-receptor binding of VLDL and LDL from apoE4 and apoE3 homozygotes.

Compared with apolipoprotein E3 (apoE3), apoE2 is less effective in mediating the binding of lipoproteins to the low-density lipoprotein (LDL) receptor. The influence of the E4 isoform, which is associated with adverse effects on plasma lipids and coronary heart disease, is less clear. We compared the ability of very low density lipoprotein (VLDL) and LDL from paired E4/4 and E3/3 subjects to compete against 125I-labeled LDL for binding with the LDL receptor on cultured fibroblasts and Hep G2 cells. The concentrations of VLDL or LDL required to inhibit binding of 125I-LDL by 50% (IC50, microgram apoB/ml) were determined, and results were assessed in terms of an IC50 ratio, E4/4 IC50 relative to E3/3 IC50, to reduce the influence of interassay variability. In Hep G2 cells, E4/4 VLDL was more effective than E3/3 VLDL in competing for the LDL receptor, the IC50 ratio being lower than unity (0.73 +/- 0.31, P < 0.05, two-tailed t-test). IC50 values themselves were marginally lower in E4/4 than E3/3 subjects (3.7 +/- 1.3 vs. 6.1 +/- 3.7, P < 0.08). However, there was no difference between E4/4 and E3/3 VLDL in competing for the LDL receptor on fibroblasts or between E4/4 and E3/3 LDL in competing for the LDL receptor on either cell type. These results suggest that inheritance of apoE4 is associated with an increased affinity of VLDL particles for LDL receptors on hepatocytes and may partly explain the influence of the E4 isoform on lipid metabolism.

Adult↗

PubMed2002

Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.

OBJECTIVE: Cloning of the ileal apical sodium-dependent bile acid transporter (ASBT) has identified a new pharmacological target for the modulation of plasma lipoproteins. The objective of this study was to determine whether a novel, specific, minimally absorbed ASBT inhibitor (SC-435) decreases LDL cholesterol through the alteration of plasma apoB kinetics. METHODS AND RESULTS: Miniature pigs were treated for 21 days with 10 mg/kg/day of SC-435 or placebo. SC-435 decreased plasma cholesterol by 9% and LDL cholesterol by 20% with no effect on other lipids. Autologous (131)I-VLDL, (125)I-LDL, and [(3)H]-leucine were injected simultaneously to determine apoB kinetics. LDL apoB concentrations decreased significantly by 10% resulting entirely from an increase in LDL-apoB fractional catabolic rate. SC-435 had no effect on either total LDL apoB production or VLDL apoB converted to LDL. SC-435 increased VLDL apoB production by 22%; however, the concentration was unchanged as a result of increased VLDL apoB direct removal. SC-435 increased hepatic mRNA and enzymatic activity for both cholesterol 7alpha-hydroxylase and HMG-CoA reductase. Hepatic LDL receptor mRNA increased significantly, whereas apoB expression was unaffected. CONCLUSIONS: A low dose of the ASBT inhibitor, SC-435, significantly reduces plasma LDL cholesterol through enhanced LDL receptor-mediated LDL apoB clearance, secondary to increased expression of cholesterol 7alpha-hydroxylase.

Animals↗

PubMed2000

Changes in plasma low-density lipoprotein (LDL)- and high-density lipoprotein cholesterol in hypo- and hyperthyroid patients are related to changes in free thyroxine, not to polymorphisms in LDL receptor or cholesterol ester transfer protein genes.

Thyroid function disorders lead to changes in lipoprotein metabolism. Both plasma low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) increase in hypothyroidism and decrease in hyperthyroidism. Changes in LDL-C relate to altered clearance of LDL particles caused by changes in expression of LDL receptors on liver cell surfaces. Changes in cholesterol ester transfer activity partly explain changes in HDL-C. It has been suggested that the magnitude of these changes is related to polymorphisms of involved genes. The aim of the present study is to investigate whether the polymorphic AvaII restriction site in exon 13 of the LDL receptor gene and the polymorphic TaqIB site in intron 1 of the cholesterol ester transfer protein are associated with the magnitude of the changes in plasma LDL-C and HDL-C, respectively, in the transition from the hypo- or hyperthyroid to the euthyroid state. From a consecutive group of 66 untreated hypothyroid and 60 hyperthyroid patients, 47 Caucasians in each group were analyzed. Fasting LDL-C and HDL-C were measured at baseline and 3 months after restoration of the euthyroid state. Genotype was determined by means of PCR techniques. The homozygous presence of a restriction site was designated as +/+, heterozygous as +/-, and absence as -/-. Trend analysis was done with ANOVA. Among hypo- or hyperthyroid patients, subgroups with different genotypes did not differ in thyroid function pre- or post treatment. The mean decrease in LDL-C (mmol/L +/- SD) in hypothyroid patients with different AvaII genotypes did not differ: - 1.07 +/- 1.44 (-/-, N = 15), -1.25 +/- 1.53 (+/-, N = 19), and -1.18 +/- 1.01 (+/+, N = 13) mmol/L [not significant (NS)]; neither did the mean increase in hyperthyroid patients: 1.07 +/- 0.90 (-/-, N = 18), 0.92 +/- 1.00 (+/-, N = 21), and 1.20 +/- 0.45 (+/+, N = 6) (NS). The mean decrease in HDL-C (mmol/L +/- SD) in hypothyroid patients with different TaqIB genotypes did not differ: -0.22 +/- 0.26 (-/-, N = 13), -0.15 +/- 0.23 (+/-, N = 21), and -0.12 +/- 0.22 (+/+, N = 9) (NS); neither did the mean increase in hyperthyroid patients: 0.29 +/- 0.39 (-/-, N = 7), 0.26 +/- 0.23 (+/-, N = 22), and 0.19 +/- 0.31 (+/+, N = 18) (NS). Changes in LDL-C and HDL-C correlated with the logarithm of the change in free T4 (fT4), expressed as the fT4 posttreatment/fT4 pretreatment ratio (r = -0.81, P < 0.001; and r = -0.62, P < 0.001, respectively). In conclusion, in the transition from hypo- or hyperthyroidism to euthyroidism, no association is found between AvaII genotype and changes in plasma LDL-C nor between TaqIB genotype and changes in HDL-C. Changes in LDL-C and HDL-C correlate with changes in fT4.

Adult↗

PubMed1998

LDL particle size and LDL and HDL cholesterol changes with dietary fat and cholesterol in healthy subjects.

We have conducted a dietary trial in 54 men and 51 women with a wide range of fasting cholesterol values to examine the use of low density lipoprotein (LDL) particle size to predict the lipoprotein response to dietary fat and cholesterol. After a 2-week low fat period, subjects were given two liquid supplements in addition to their low fat diet for 3 weeks each, one containing 31-40 g of fat and 650-845 mg of cholesterol, the other fat free. LDL particle type was determined by 3-15% gradient gel electrophoresis. On multiple regression, LDL type was independently related to plasma triglyceride (P < 0.001), waist circumference (P < 0.01), and high density lipoprotein (HDL) (P < 0.001) accounting for 56% of the variance in LDL type in the whole group. Change in LDL cholesterol with dietary fat and cholesterol was unrelated to LDL particle size in either men or women. However, change in HDL cholesterol in men was strongly related to LDL particle type (r = -0.52, P = 0.001) and change in HDL2 cholesterol in women was related to LDL particle type (r = -0.40, P < 0.01). In conclusion, we are unable to confirm the finding that LDL particle type can predict changes in LDL cholesterol following changes in dietary fat intake. However, LDL particle type can independently predict changes in HDL cholesterol in men and accounts for 27% of the variance.

Adult↗

PubMed1994

Regulation of heparin binding-epidermal growth factor like growth factor gene expression by LDL and oxidized-LDL in rat mesangial cells.

The present study was to determine whether low-density lipoprotein (LDL) and oxidized LDL (Ox-LDL) modulate the heparin binding-epidermal growth factor like growth factor (HB-EGF) gene expression in rat mesangial cells (RMC). Using Northern blot analysis, LDL and Ox-LDL stimulated the expression of RMC HB-EGF mRNA in a time- and concentration-dependent manner, and the stimulatory effect of Ox-LDL lasted longer than LDL. In addition, a protein kinase C (PKC) inhibitor-staurosporine and a PKC-depletion condition abolished both of the stimulatory activities of LDL and Ox-LDL, while H-8 (a protein kinase A inhibitor) and cAMP-antagonist (cyclic adenosine-3':5'-monophosphothioate) had little effect. Our data indicate that LDL and Ox-LDL enhance HB-EGF gene expression and both via the PKC pathway in RMC. As HB-EGF is a mitogen for RMC, our results suggest that lipoproteins may regulate RMC function by inducing HB-EGF gene expression and thus contribute to glomerular injury.

Alkaloids↗

PubMed1997

Anti-modified LDL antibodies and LDL-containing immune complexes in IDDM patients and healthy controls.

Antibodies to oxidized LDL (ox-LDL) and LDL-containing immune complexes (LDL-IC) have been reported to be associated with the presence or progression of arteriosclerosis. We screened for anti-modified LDL antibodies and isolated soluble IC by precipitation with 3.5% (w/v) polyethylene glycol (PEG) 6000 in two groups. The patient group was constituted by 16 insulin-dependent diabetes mellitus subjects free of macrovascular complications. The control group was constituted by 16 healthy, age-, gender-, race-, and body mass index-matched nondiabetic subjects. We detected anti-ox-LDL antibodies and anti-malondialdehyde-modified LDL antibodies with similar levels in patients and controls, while the levels of anti-glycated LDL antibodies were very low, but slightly higher in diabetics than in healthy controls. Isolated LDL-IC were adsorbed to red blood cells (RBC) and incubated with human macrophages for 18 hr at 37 degrees C. Under those experimental conditions, RBC-adsorbed IC are taken up by macrophages but the RBC remain intact and are not ingested. Slightly higher levels of cholesteryl ester (CE) accumulation were measured in macrophages incubated with RBC to which we adsorbed IC isolated from diabetics (15.4 +/- 2.5 micrograms/mg of protein, mean +/- SEM) than in macrophages incubated with IC isolated from controls (12.5 +/- 1.6 micrograms/mg of protein, mean +/- SEM), but the difference did not reach statistical significance. PEG-precipitable IC isolated from both normal and diabetic subjects led, in some instances, to the transformation of macrophages into foam cells. Significant correlations were observed between CE accumulation and the content of apo B (P < 0.0001), total cholesterol (P = 0.0004), IgG (P = 0.015), and IgA (P = 0.015) in the isolated IC. The correlation between CE accumulation and the content of apo B in isolated IC was stronger in diabetics than in the control group (r = 0.759 vs r = 0.500). Fractionation of isolated IC in immobilized protein A/G yielded immunoglobulin-rich fractions which contained cholesterol and IgG anti-ox-LDL antibodies. The cholesterol content of these fractions was significantly correlated (P = 0.001) with CE accumulation. In conclusion, both diabetics and normal individuals have circulating IC whose atherogenic potential appears to be related to the presence of LDL and antibodies of the IgG and IgA isotypes.

Adult↗

PubMed1986

Low-density lipoprotein (LDL) and lymphocyte responses: direct suppression by native LDL and indirect inhibition from zinc chelation by contaminating EDTA.

Low-density lipoproteins (LDL) have been shown to have a number of effects on the function of various cell types. To appreciate whether the in vitro effects of LDL have in vivo relevance, it is necessary to demonstrate that the biologic action described can be accounted for by native LDL and not by an alteration in the molecule or an addition to the preparation occurring during isolation. EDTA is frequently added to LDL during preparation to prevent oxidation. The effect of EDTA dialysis on LDL-mediated inhibition of lymphocyte responses was therefore examined. LDL alone did not inhibit mitogen-induced initial lymphocyte activation but rather suppressed lymphocyte DNA synthesis and subsequent proliferation in a transferrin-reversible manner. LDL dialysed with EDTA also inhibited lymphocyte responsiveness but the inhibition was not reversed by transferrin. Further experiments demonstrated that after dialysis EDTA in the LDL accounted for the change in its inhibitory effects. EDTA did not alter the lipoprotein but itself inhibited lymphocyte responses by chelating zinc necessary for DNA synthesis. These data indicate that LDL preparations may exhibit at least two separate effects on lymphocyte function. LDL is directly suppressive, while small amounts of contaminating EDTA can additionally be suppressive by chelating zinc. Thus, EDTA present in LDL preparations can alter their apparent biologic effects.

Adult↗