| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Plasmin and kallikrein reduce HDL-induced cholesterol efflux from foam cells Lindstedt, L. and P. T. Kovanen (2000), Biochem Biophys Res Commun 277(3): 552-7. Abstract: Arterial intima contains metabolically active factors such as proteases, which may act on high-density lipoprotein (HDL) and impair its ability to accept cholesterol. In this study we treated human HDL(3) with human plasmin and human plasma kallikrein, two proteases also found in the human arterial intima, in order to study their effect on the ability of HDL(3) to promote cholesterol efflux from human macrophage foam cells. After exposure to plasmin or plasma kallikrein for 15 min, HDL(3) showed a decrease of about 60% in its ability to promote cholesterol efflux from the macrophage foam cells. SDS-PAGE analysis of the degraded HDL(3) particles showed that plasmin had generated cleavage products less than 15 kDa in size and plasma kallikrein had generated a major product of about 19 kDa. However, there was only a slight loss of intact apolipoproteins, suggesting degradation of a small subpopulation of HDL(3) particles. Agarose gel electrophoresis showed that a decrease in cholesterol efflux was accompanied by total loss of the HDL(3) with prebeta-mobility, but no apparent change in those with alpha mobility. These results suggest that the presence of active plasmin or plasma kallikrein in the atherosclerotic arterial intima promotes atherogenesis by blocking cholesterol efflux from macrophage foam cells. |
| Plasminogen activator inhibitor-1 and relations to fatty acid composition in the diet and in serum cholesterol esters Byberg, L., A. Smedman, et al. (2001), Arterioscler Thromb Vasc Biol 21(12): 2086-92. Abstract: High plasminogen activator inhibitor (PAI)-1 levels and poor dietary fat quality are potential risk factors for cardiovascular disease. The aim was to investigate the cross-sectional associations between PAI-1 activity and dietary nutrient intake, focusing on fat quality, in a population-based study of 871 men aged 70 years. The relationship between PAI-1 and the fatty acid composition in serum cholesterol esters (n=381 men) was also studied. The estimated total fat intake was positively associated with PAI-1 activity. The intake of both monounsaturated and polyunsaturated fatty acids was positively associated with PAI-1 activity, whereas the intake of saturated fatty acids was not. In serum cholesterol esters, higher proportions of palmitoleic and dihomo-gamma-linolenic acid, a lower proportion of linoleic acid, and reduced estimated Delta5-desaturase activity were associated with higher PAI-1 levels. These associations were confounded by factors representing the insulin resistance syndrome. PAI-1 activity was positively associated with gamma-linolenic and arachidonic acid, independent of potential confounders. In conclusion, this study demonstrates that dietary intake of unsaturated fatty acids is positively associated with PAI-1 activity, whereas intake of saturated fatty acids is not. The associations present between PAI-1 activity and the fatty acid proportions in serum cholesterol esters are partly influenced by metabolic syndrome-related factors. |
| Platelet aggregation and HDL cholesterol are predictive of acute coronary events in heart transplant recipients de Lorgeril, M., P. Boissonnat, et al. (1994), Circulation 89(6): 2590-4. Abstract: BACKGROUND: Sudden death (SD) and acute myocardial infarction (AMI) are the main complications limiting long-term survival after heart transplantation (HT). They are unpredictable and, at present, unpreventable. Platelet aggregation (PA) has recently emerged as a significant prognostic indicator in nontransplanted coronary disease patients. The main purpose of the present study was to evaluate to what extent PA could predict SD and AMI in long-term survivors of HT independently of serum lipid levels. METHODS AND RESULTS: We studied 207 patients. All received triple immunosuppressive therapy. During follow-up, the incidence of SD and AMI was determined, and the independent role of PA as predictor was evaluated with other usual risk factors by a Cox multivariate regression model. There were 11 SDs and 14 AMIs after an average follow-up of 642 days, giving an average incidence rate of 7.3 events per year per hundred patients. By univariate analysis, the most potent predictors were ADP-induced platelet aggregation (positive association) and total cholesterol (negative association). Age and length of time since transplant were not predictors. By multivariate analysis, only the secondary wave of ADP-induced platelet aggregation (P =.001) and high-density lipoprotein cholesterol (P =.03) were independent predictors. The relative risk of SD or AMI based on a comparison between patients with high (> 36%) or low (< 36%) ADP-induced platelet aggregation was 4.3 (95% confidence interval, 1.9 to 9.5, P =.0001). CONCLUSIONS: This study provides the first demonstration of an association between increased platelet aggregation and subsequent SD or AMI in HT recipients. It suggests that platelets and thrombosis also are implicated in the pathogenesis of AMI and SD in HT recipients. Identification of a safe and effective antiplatelet therapy should be actively pursued. |
| Platelet deposition at high shear rates is enhanced by high plasma cholesterol levels. In vivo study in the rabbit model Badimon, J. J., L. Badimon, et al. (1991), Arterioscler Thromb 11(2): 395-402. Abstract: We have studied the effects of high plasma cholesterol levels on platelet-vessel wall interactions under high shear rate conditions typical of the apex of stenotic arteries (2,600 sec-1). Hypercholesterolemia was induced by feeding rabbits a 0.5% cholesterol-rich diet for 60 days. Platelet deposition was studied by use of an annular perfusion chamber and de-endothelialized abdominal rabbit aortas as substrates. After ingestion of the atherogenic diet, the experimental group of animals developed severe hypercholesterolemia, platelets became more fluid as determined by steady-state fluorescence anisotropy (p less than 0.05), and red blood cell deformability was decreased (p less than 0.001) when compared with normal controls. The fatty acid composition of platelet membranes showed an increase in the percentage of the long-chain saturated fatty acids (palmitic, C16:0, and stearic, C18:0) that may account for the lower polyunsaturated/saturated fatty acid ratio observed in the hyperlipemic animals. Total platelet deposition was significantly increased (p less than 0.05) in the hyperlipemic group as compared with the control group at 5 minutes' perfusion time, becoming less evident at 20 minutes' perfusion time. Our results suggest that the presence of hyperlipidemia may contribute to acute thrombosis by enhancing platelet-vessel wall interaction. |
| Platelet hypersensitivity in cholesterol-fed rabbits: enhancement of thromboxane A2-dependent and thrombin-induced, thromboxane A2-independent platelet responses Gross, P. L., M. L. Rand, et al. (1991), Atherosclerosis 88(1): 77-86. Abstract: Hypercholesterolemia (mean plasma cholesterol: 15 mM) was induced in rabbits by the feeding of a chow diet enriched with a low amount (0.25%, w/w) of cholesterol only. Platelet size and protein content decreased significantly, but the whole blood platelet count did not change. The platelets became enriched in cholesterol, as indicated by a significant increase in the cholesterol:phospholipid molar (C/P) ratio. Specific responses of washed platelets stimulated with various agonists were studied to determine the effects of hypercholesterolemia on the various pathways of platelet aggregation in the absence of plasma components. In platelets from hypercholesterolemic rabbits compared with controls: aggregation induced by ADP was not altered; collagen-induced responses (aggregation, secretion of 14Cserotonin from prelabelled platelets, thromboxane A2 (TXA2) formation, mobilization of 3Harachidonate from prelabelled platelets) were enhanced; with aspirin-treated platelets, aggregation induced by the TXA2 mimetic U46619 was enhanced: and thrombin-induced responses of both untreated platelets (aggregation, secretion of granule contents, TXA2 formation) and aspirin-treated platelets (aggregation) were enhanced. Thus, platelets from cholesterol-fed rabbits not only form more TXA2, but they aggregate more extensively when stimulated by its mimetic. In addition, it has not been previously recognized that these platelets are also hypersensitive to thrombin-induced aggregation that is independent of TXA2. |
| Platelet reactivity and arachidonic acid metabolism in type II hyperlipoproteinaemia and its modification by cholesterol-lowering agents Schror, K. (1990), Eicosanoids 3(2): 67-73. Abstract: A significant percentage of patients suffering from a selective increase in plasma LDL cholesterol (type IIa hyperlipoproteinaemia) exhibits increased platelet reactivity. This includes enhanced platelet responsiveness against a variety of platelet-stimulating agents ex vivo and enhanced arachidonic acid metabolism associated with increased generation of arachidonic acid metabolites (thromboxane A2, 12-HETE) and secretion of platelet-storage products. It is possible, but not proven, that an elevated cholesterol content in the platelet membranes forms a common denominator for these responses. Agents that lower total plasma or LDL cholesterol in hypercholesterolaemic patients by interfering with cholesterol reabsorption from the gut (cholestyramine, cholestipol) or reduction of hepatic VLDL release (fibrates) do not appear to interfere with platelet hyperreactivity and do not change platelet-derived thromboxane formation. There is also no correlation with the action of these agents on total plasma and LDL cholesterol. A different situation might exist with inhibitors of the HMG-CoA reductase, which have been found to reduce platelet hyperreactivity and thromboxane formation. However, this finding requires further confirmation in controlled, prospective, large trials. There is increasing evidence that patients with type II hyperlipoproteinaemia have a significant (by about 50%) reduced number of specific prostacyclin binding sites at the platelet membrane that might be involved in the reduced inhibition of platelet function by prostacyclin. Normalization of the reduced responsiveness against prostacyclin has also been demonstrated for cholestyramine and simvastatin. However, so far this issue has not been addressed for the other lipid-lowering compounds. |
| Platelet secreted lipoprotein-like particle is taken up by the macrophage scavenger receptor and enhances cellular cholesterol accumulation Maor, I., G. J. Brook, et al. (1991), Atherosclerosis 88(2-3): 163-74. Abstract: Enhanced macrophage cholesterol accumulation is associated with foam cell formation in the atherosclerotic lesion. Since platelet activation plays an important role in atherogenesis, we questioned whether products released from activated platelets could affect macrophage cholesterol metabolism. The addition of platelet-conditioned medium (PCM, obtained from collagen activated platelets) to a J-774 macrophage cell line, enhanced cellular cholesteryl ester content by 32%. The cholesterol esterification rate was also increased by 29%. Pre-loading the macrophages with cholesterol by incubation with acetyl-LDL, resulted in a further elevation of 48% in PCM-mediated cholesterol esterification. Possible mechanisms for the enhanced cholesterol esterification by J-774 macrophages following incubation with PCM include increased cholesterol influx and/or decreased cholesterol efflux (These cells were recently shown not to synthesize cholesterol). However, both increased uptake of PCM cholesterol by the macrophages as well as increased cellular cholesterol efflux (by 22%) were noted. The enhancement of cholesterol esterification by PCM was competitively inhibited by fucoidin and polyinosinic acid, implicating PCM binding to the scavenger receptor. This was further evidenced by the observations that apolipoprotein E which reduces cellular uptake via the scavenger receptor but not via the LDL receptor, also inhibited the effect of PCM, whereas IgG C-7, the LDL receptor antibody, did not alter the effect of PCM. Lysosomal involvement in the cellular processing of PCM was observed since PCM activity was inhibited by the lysosomal inhibitor, chloroquine. Partial purification of PCM by gel filtration revealed that the cholesterol component was associated with both phospholipids and proteins in a lipoprotein-like particle. Delipidation of PCM resulted in its inactivation but both heat treatment and tryptic digestion of PCM, revealed that the protein (and not only the cholesterol) component was also essential for the effect of PCM on cellular cholesterol esterification. Furthermore, PCM prepared from platelets of a patient with Gray Platelet Syndrome that lack platelet alfa granules (which contain platelet specific proteins), failed to enhance cholesterol esterification. These results demonstrate that lipoprotein-like particles released during platelet activation can interact with the macrophage scavenger receptor thus leading to enhanced cellular cholesterol accumulation. |
| Platelet-derived growth factor receptor inhibition reduces allograft arteriosclerosis of heart and aorta in cholesterol-fed rabbits Sihvola, R. K., J. M. Tikkanen, et al. (2003), Transplantation 75(3): 334-9. Abstract: BACKGROUND: Crosstalk between pro-inflammatory cytokines and platelet-derived growth factor (PDGF) regulates smooth-muscle-cell proliferation in cardiac-allograft arteriosclerosis. In this study, we tested the effect of STI 571, a novel orally active protein tyrosine kinase (PTK) inhibitor selective for PDGF receptor (PDGF-R) on transplant and accelerated arteriosclerosis in hypercholesterolemic rabbits. METHODS: Cardiac allografts were transplanted heterotopically from Dutch Belted to New Zealand White rabbits. A 0.5% cholesterol diet was begun 4 days before transplantation. Recipients received STI 571 5 mg/kg per day or vehicle intraperitoneally throughout the study period of 6 weeks. Cyclosporine A was given as background immunosuppression. RESULTS: In cardiac allografts of vehicle-treated rabbits, 76.2+/-2.1% of medium-sized arteries were affected by intimal thickening, and the percentage of arterial occlusion was 45.0+/-5.0%. Treatment with STI 571 reduced the incidence of affected medium-sized arteries to 41.2+/-8.1% (P <0.05) and the arterial occlusion to 27.6+/-5.0% (P<0.05). In addition, we observed that STI 571 treatment reduced intimal lesion formation in proximal ascending aorta of transplanted hearts from 72.3+/-19.9 to 12.7+/-1.9 microm (P<0.05). Our results also show that STI 571 significantly inhibited accelerated arteriosclerosis in medium-sized arteries of recipients' own hearts. CONCLUSIONS: The results of the present study suggest that PDGF-R activation may regulate the development of transplant and accelerated arteriosclerosis in hypercholesterolemic rabbits. Thus, PTK inhibitors may provide new strategies for prevention of these fibroproliferative vascular disorders. |
| Pleiotropic genetic effects on LDL size, plasma triglyceride, and HDL cholesterol in families Edwards, K. L., M. C. Mahaney, et al. (1999), Arterioscler Thromb Vasc Biol 19(10): 2456-64. Abstract: The interrelationships among low density lipoprotein (LDL) particle size, plasma triglyceride (TG), and high density lipoprotein cholesterol (HDL-C) are well established and may involve underlying genetic influences. This study evaluated common genetic effects on LDL size, TG, and HDL-C by using data from 85 kindreds participating in the Genetic Epidemiology of Hypertriglyceridemia (GET) Study. A multivariate, maximum likelihood-based approach to quantitative genetic analysis was used to estimate the additive effects of shared genes and shared, unmeasured nongenetic factors on variation in LDL size and in plasma levels of TG and HDL-C. A significant (P<0.001) proportion of the variance in each trait was attributable to the additive effects of genes. Maximum-likelihood estimates of heritability were 0.34 for LDL size, 0.41 for TG, and 0.54 for HDL-C. Significant (P<0.001) additive genetic correlations (rho(G)), indicative of the shared additive effects of genes on pairs of traits, were estimated between all 3 trait pairs: for LDL size and TG rho(G)=-0.87, for LDL size and HDL-C rho(G)=0.65, and for HDL-C and TG rho(G)=-0.54. A similar pattern of significant environmental correlations between the 3 trait pairs was also observed. These results suggest that a large proportion of the well-documented correlations in LDL size, TG, and HDL-C are likely attributable to the influence of the same gene(s) in these families. That is, the gene(s) that may contribute to decreases in LDL size also contribute significantly to higher plasma levels of TG and lower plasma levels of HDL-C. These relationships may be useful in identifying genes responsible for the associations between these phenotypes and susceptibility to cardiovascular disease in these families. |
| Pleural cholesterol in differentiating transudates and exudates. A prospective study of 232 cases Gil Suay, V., E. Martinez Moragon, et al. (1995), Respiration 62(2): 57-63. Abstract: Two hundred and four patients with pleural effusion were studied to investigate the utility of Light's criteria and pleural fluid cholesterol level (pCHOL) in the identification of exudative pleural effusion (EPE) and transudative pleural effusion (TPE). There were 48 TPE, 56 tumor, 47 tuberculous, 30 metapneumonic and 23 miscellaneous patients. A value > or = 54 mg/dl for pCHOL and > or = 0.32 for the pleura/serum cholesterol ratio (p/sCHOL) showed sensitivity (S) and specificity (Sp) of 95.5% and 91.6% for pCHOL, and 97.4% and 91.6% for p/sCHOL, respectively. Combined pCHOL and/or p/sCHOL showed a S of 98.7% and Sp of 89.5%. Light's criteria achieved a S of 100% and Sp of 64.5%. Combined pCHOL and p/sCHOL revealed a similar accuracy to Light's criteria in EPE diagnosis but was found to be more exact in TPE diagnosis. |
| Pleural cholesterol: a useful determination Paredes Arranz, C., F. del Campo Matias, et al. (1991), Rev Clin Esp 189(1): 3-7. Abstract: The difference between exudates and transudates is the first question a clinician must solve when facing a pleural effusion. A great number of parameters have been tried without a definite efficacy of any of them. Cholesterol is an easy, useful determination for distinguishing exudates from transudates. In our series of 86 patients a cholesterol value of 50 mg/dl allowed us to correctly classify 94.2% of effusions. The ratio between pleural fluid cholesterol/serum cholesterol was more efficient because it permitted to correctly classify 97.7% of effusions, in one of those major groups which constitute the binomial exudate/transudate. |
| Pleural effusion in patients with systemic cholesterol embolization Kollef, M. H., M. T. McCormack, et al. (1993), Chest 103(3): 792-5. Abstract: We evaluated two patients with systemic cholesterol embolization (SCE) associated with the development of pleural effusions. These two patients had evidence of atherosclerosis and presented with livedo reticularis, renal insufficiency, and gangrenous cutaneous changes as manifestations of their SCE. In both cases, closed pleural biopsies demonstrated acute inflammation of the parietal pleura. Our experience with these individuals and a review of the medical literature suggest that pleural injury from atheromatous embolization may occur. Physicians caring for patients with SCE should be aware of the possible association of pleural reactions with this process. |
| Pleural fluid cholesterol and lactate dehydrogenase for separating exudates from transudates Garcia-Pachon, E. and I. Padilla-Navas (1996), Chest 110(5): 1375-6. |
| Poland and United States Collaborative Study on Cardiovascular Epidemiology. A comparison of HDL cholesterol and its subfractions in populations covered by the United States Atherosclerosis Risk in Communities Study and the Pol-MONICA Project Broda, G., C. E. Davis, et al. (1996), Arterioscler Thromb Vasc Biol 16(2): 339-49. Abstract: HDL cholesterol (HDL-C) levels are inversely related to coronary heart disease (CHD) risk, and HDL-C distributions vary among countries. Poland is one of the few developed countries in which CHD rates are increasing at the same time that US rates have been falling, but whether these differences are explained by differences in risk factors such as HDL-C has not been determined. To examine this possibility, levels of HDL-C and its subfractions were compared in US and Polish urban and rural men and women aged 45 to 64 years. Age-adjusted HDL-C means were 0.20 mmol/L higher in urban Polish men and 0.37 mmol/L higher in rural Polish men than in their US counterparts (P <.0001); means in urban Polish women were 0.06 mmol/L higher (P <.05) and in rural Polish women 0.09 mmol/L higher (P <.001) than in their US counterparts. Adjustment for age, education, alcohol intake, smoking, BMI, heart rate, and menopause status (in women) had little effect on differences. Means of HDL2 and HDL3 levels showed similar between-country differences, although differences were minimal for HDL2 in urban men and women, and HDL3 means did not differ between rural women. BMI was inversely related to HDL-C and both subfractions in all gender-country-site strata (P <.001), and alcohol was directly related to HDL-C (P <.001) in all strata except Polish women. Cigarette smoking was negatively related to HDL-C and both subfractions in all US samples except HDL2 in urban men, whereas in Polish samples, significant associations were found only in urban women for HDL-C and in rural and urban women for HDL3. Age, heart rate, and education showed inconsistent or no association with HDL-C and its subfractions in either country. This profile of HDL-C and its subfractions in Polish samples contrasts sharply with the opposite trend in CHD mortality rates, which suggests either that other risk factors may account for the trends or that the relationship between HDL-C and CHD may differ between the two countries. |
| Polarized cholesterol and phospholipid efflux in cultured gall-bladder epithelial cells: evidence for an ABCA1-mediated pathway Lee, J., A. Shirk, et al. (2002), Biochem J 364(Pt 2): 475-84. Abstract: Gall-bladder epithelial cells (GBEC) are exposed to high concentrations of cholesterol in bile. Whereas cholesterol absorption by GBEC is established, the fate of this absorbed cholesterol is not known. The aim of this study was to determine whether ABCA1 (ATP-binding cassette transporter A1) mediates cholesterol efflux in GBEC. Polarized canine GBEC were cultured on porous membrane filters allowing separate access to apical (AP) and basolateral (BL) compartments. After AP loading of cells with model bile and 14Ccholesterol, cholesterol efflux was measured. Cholesterol loading together with 8-bromo-cAMP treatment, which increased ABCA1 expression, led to a significant increase in cholesterol efflux with apolipoprotein A-I (apoA-I) as the acceptor. Cholesterol efflux was observed predominantly into the BL compartment. Similar results were found for phospholipid efflux. Confocal immunofluorescence microscopy showed a predominantly BL ABCA1 localization. Interestingly, apoA-I added to either the AP or the BL compartments elicited BL lipid efflux with cAMP treatment. No paracellular or transcellular passage of 125I-apoA-I occurred. Ligands for the nuclear hormone receptors liver X receptor alpha (LXRalpha) and retinoid X receptor (RXR) elicited AP and BL cholesterol efflux, suggesting the involvement of both ABCA1- and non-ABCA1-mediated pathways. In summary, BL cholesterol/phospholipid efflux consistent with an ABCA1-mediated mechanism occurs in GBEC. This efflux pathway is stimulated by cAMP and by LXRalpha/RXR ligands, and in the case of the cAMP pathway appears to involve a role for biliary apoA-I. |
| Policosanol inhibits cholesterol biosynthesis and enhances low density lipoprotein processing in cultured human fibroblasts Menendez, R., S. I. Fernandez, et al. (1994), Biol Res 27(3-4): 199-203. Abstract: Policosanol is a mixture of aliphatic primary alcohols isolated and purified from sugar cane wax, that induces cholesterol-lowering effects in experimental models and human beings. When human lung fibroblasts were incubated with policosanol for 48 hours prior to the experiment, a dose dependent inhibition of 14C-acetate incorporation into total cholesterol was observed, whereas labeled mevalonate incorporation was not inhibited. Even when cholesterol synthesis was not strongly inhibited, low density lipoprotein (LDL) processing was markedly enhanced. Thus, LDL binding, internalization and degradation were significantly increased after policosanol treatment. In addition, despite the fact that'cholesterol generation was not inhibited at the lowest dose of policosanol assayed, LDL processing was significantly increased. The current data indicate that policosanol inhibits cholesterol synthesis at the earliest steps of the cholesterol biosynthetic pathway. On the other hand, this study suggests that the increase in LDL processing may be partially explained by the inhibition of cholesterol biosynthesis, even though an sterol-independent mechanism might be responsible for the enhancement of LDL-receptor activity. |
| Poloxamer 407-mediated changes in plasma cholesterol and triglycerides following intraperitoneal injection to rats Wout, Z. G., E. A. Pec, et al. (1992), J Parenter Sci Technol 46(6): 192-200. Abstract: Poloxamer (Pluronic) nonionic surfactant vehicles are a series of chemically-related block copolymers finding widespread use in parenteral formulations as solubilizing and wetting agents for traditional, low-molecular weight organic drug molecules, as well as stabilizing agents for proteins and polypeptide drugs. We report the effects of poloxamer 407 (Pluronic F-127) on plasma cholesterol and triglyceride concentrations in rats. Poloxamer 407 injected into rats by intraperitoneal injection (dose = 1.5 gm/kg) resulted in sustained (greater than 96 hour) hypercholesterolemia and hypertriglyceridemia. A larger dose of poloxamer 407 was required to elevate plasma triglyceride relative to total cholesterol. Ingestion of commercial rat chow had a negligible effect on plasma cholesterol and triglycerides levels in control (no poloxamer injection) animals, but consumption of food by animals that received an intraperitoneal injection of poloxamer 407 (30% w/w) resulted in significantly (p <.05) greater elevations in plasma cholesterol and triglycerides than in fasted animals administered poloxamer 407. The route of poloxamer 407 administration, namely intramuscular vs. intraperitoneal injection, was observed to be a more important factor for poloxamer-induced elevations in plasma cholesterol than poloxamer-mediated elevations in plasma triglycerides. Our results also provide suggestive evidence that the mechanism responsible for the elevation of plasma cholesterol following intraperitoneal injection of a poloxamer 407 solution (30% w/w) to rats may be due to stimulation of 3-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase activity in the liver by the poloxamer vehicle.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Poly(ethylene glycol) derivative of cholesterol reduces binding step of liposome uptake by murine macrophage-like cell line J774 and human hepatoma cell line HepG2 Ishiwata, H., S. B. Sato, et al. (1998), Chem Pharm Bull (Tokyo) 46(12): 1907-13. Abstract: Liposome uptake by HepG2 human hepatoma cells was investigated in comparison with the uptake by J774 murine macrophage-like cells. HepG2 cells accumulated liposomes (egg yolk phosphatidylcholine (EPC)/Chol; 75/25, diameter 0.2 micron) at 37 degrees C comparably to J774 macrophage-like cells. Confocal microscopic observations revealed that J774 cells internalized EPC/Chol liposomes efficiently but HepG2 cells kept most of the liposomes bound on their plasma membrane surfaces. Poly(ethylene glycol) (PEG)-coated liposomes (0.2 micron) containing poly(ethylene glycol) cholesteryl ether (PEG-Chol) avoided cellular uptake at 37 degrees C by either cell line. In both cell lines, binding of PEG-coated liposomes was lower than that of EPC/Chol liposomes when incubation was carried out at 4 degrees C. To analyze the binding process at 37 degrees C, surface-bound liposomes were removed from the cells by pronase treatment. A reduction of the amount of bound-liposomes on cell surfaces was observed in the case of PEG-coated liposomes. Therefore, PEG-coating reduces direct binding of liposomes to the cell surfaces. The presence of apolipoprotein E (apoE) increased the uptake to EPC/Chol liposomes via its receptor in both cell lines. In contrast, cellular uptake of PEG-coated liposomes was not enhanced by treatment with apoE. Therefore, while apoE-mediated liposome uptake occurs in the case of EPC/Chol liposomes, it does not occur for PEG-coated liposomes; PEG-coating also inhibits protein-mediated binding to the cells. These results further imply that elusion from liver clearance of PEG-coated liposomes is not only due to the reduction of uptake by Kupffer cells but also by hepatocytes when liposomes are small enough to go through the fenestrates of the endothelial lining. |
| Poly(N,N,N-trimethylammoniumalkyl acrylamide chloride) based hydrogels for serum cholesterol reduction Cameron, N. S., F. G. Morin, et al. (2004), Biomacromolecules 5(1): 24-31. Abstract: Hydrogels present an attractive alternative to nanoscale block copolymer aggregates and microscale resin beads as potential asystemic serum cholesterol reduction materials. Not only would the oral delivery of these materials be more pleasant than the sand-like bile salt anion sequestrant beads but also the hydrogel preparation is much simpler than the copolymer aggregate analogues Cameron, N. S.; Eisenberg, A.; Brown, G. R. Biomacromolecules 2002, 3, 116-123. Cameron, N. S.; Eisenberg, A.; Brown, G. R. Biomacromolecules 2002, 3, 124-132. Our goal was to explore these materials building on our experience with bulk resins and self-assembled copolymers. In this paper, following a brief introduction to hydrogels and their application to hypercholesterolemia, the synthesis, characterization, and preliminary glycocholate binding properties of poly(N,N,N-trimethylammoniumalkyl acrylamide chloride)gel are presented Cameron, N. S.; Eisenberg, A.; Brown, G. R. Polym. Preprints 2002, 43, 771-772. |
| Polyenylphosphatidylcholine decreases alcoholic hyperlipemia without affecting the alcohol-induced rise of HDL-cholesterol Navder, K. P., E. Baraona, et al. (1997), Life Sci 61(19): 1907-14. Abstract: In ethanol-fed rats, supplementation of the diet with soybean polyenylphosphatidylcholine (3 g/liter for 21 days) markedly decreased postprandial VLDL-triglycerides and both VLDL- and LDL-cholesterol levels, whereas it maintained high levels of HDL-cholesterol, compared to an equivalent intake of choline and polyunsaturated fatty acids. By contrast, there were no changes in the serum lipoproteins of the pair-fed controls. The prevention of alcoholic hypertriglyceridemia was associated with marked attenuation of the alcoholic fatty liver and it occurred despite a slight increase in fat absorption. Thus, the administration of polyenylphosphatidylcholine not only attenuates the hepatotoxicity of ethanol, but also increases the HDL/LDL cholesterol ratio, which may be beneficial for the prevention of atherosclerosis and coronary heart disease. |