| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Deoxycholic acid in gall bladder bile does not account for the shortened nucleation time in patients with cholesterol gall stones Noshiro, H., K. Chijiiwa, et al. (1995), Gut 36(1): 121-5. Abstract: The relations between the concentration of deoxycholic acid (DCA), the cholesterol saturation index, and the nucleation time in gall bladder bile were measured to determine the role of DCA in bile in the pathogenesis of cholesterol gall stone disease. Bile was obtained from patients with cholesterol gall stones (n = 30), subjects without gall stones (n = 35), and patients with pigment gall stones (n = 9). Three of 30 cholesterol gall stone patients and 10 of 35 gall stone free subjects were treated with antibiotics by mouth to decrease the concentration of bile DCA and determine the effect of DCA on biliary lithogenecity. Both the percentage and concentration of DCA in bile were similar in patients with and without cholesterol gall stones despite significant differences in their cholesterol saturation indices and nucleation times. Neither the percentage nor the concentration of DCA in bile correlated with either the cholesterol saturation index or the nucleation time. Analysis of subgroups with matching cholesterol saturation indices showed no correlation between the proportion of DCA in the bile and the cholesterol nucleation time. The proportion of DCA in bile was decreased by antibiotic treatment, but this had no effect on the cholesterol saturation index or nucleation time. These results suggest that DCA in bile is not responsible for biliary cholesterol saturation or cholesterol nucleation time. |
| Deoxycholic acid influences cholesterol solubilization and microcrystal nucleation time in gallbladder bile Hussaini, S. H., S. P. Pereira, et al. (1995), Hepatology 22(6): 1735-44. Abstract: Little is known about the effects of biliary deoxycholic acid on the partitioning of biliary cholesterol between vesicles and micelles and on the rate of nucleation of cholesterol microcrystals, key steps in gallstone formation. Therefore, 43 samples of fresh gallbladder bile were obtained from a heterogeneous group of patients with and without stones. Univariate and multivariate analyses were then applied to determine the inter-relationships between biliary cholesterol saturation, total lipid concentration, and bile acid species and (1) the distribution of biliary cholesterol between vesicles and micelles and (2) the cholesterol microcrystal nucleation time. The percentage of deoxycholic acid in bile was shown to be linearly related to the cholesterol saturation index (r =.54; P <.001), the vesicular cholesterol:phospholipid molar ratio (r =.53; P <.001), and the molar concentration of cholesterol in the vesicles (r =.59; P <.001). The mean proportion of biliary deoxycholic acid conjugates was also greater in patients with rapid nucleation times (23.4 +/- SEM 1.1%) than in those with slow nucleation times (17.3 +/- 1.9%; P <.05). As total bile lipid concentration increased, the proportion of total biliary cholesterol in vesicles decreased (r =.53; P <.001), whereas the molar concentration of vesicular cholesterol increased (r =.42, P <.01). The cholesterol saturation indices, total bile lipid concentration, and proportion of biliary deoxycholate were independent determinants of the molar concentration of cholesterol in vesicles. We conclude that relative increases in the percentage of deoxycholic acid and in bile lipid concentration, favor the partitioning of cholesterol into vesicles. In turn, this leads to an increase in the vesicular cholesterol:phospholipid molar ratio and thus to a decrease in the cholesterol microcrystal nucleation time. |
| Deoxycholic acid treatment in patients with cholesterol gallstones: failure to detect a suppression of cholesterol 7alpha-hydroxylase activity Hillebrant, C., B. Nyberg, et al. (1999), J Intern Med 246(4): 399-407. Abstract: Hillebrant C-G, Nyberg B, Angelin B, Axelson M, Bjorkhem I, Rudling M, Einarsson C (Huddinge University Hospital and Karolinska Hospital, Karolinska Institute, Stockholm, Sweden). Deoxycholic acid treatment in patients with cholesterol gallstones: failure to detect a suppression of cholesterol 7alpha-hydroxylase activity. J Intern Med 1999; 246: 399-407. OBJECTIVES: Based on animal studies, hydrophobic bile acids have been postulated to be particularly strong inhibitors of bile acid synthesis. The present study was undertaken to characterize in humans the effects of one of the most hydrophobic of the common bile acids, deoxycholic acid (DCA), on the transcriptional regulation and activity of the cholesterol 7alpha-hydroxylase, on hepatic cholesterol metabolism and on biliary lipid metabolism and plasma lipids. DESIGN, SUBJECTS AND SETTINGS: Thirteen patients with cholesterol gallstone disease were treated with DCA (750 mg day-1) for 3 weeks prior to cholecystectomy. Blood samples were collected before and during treatment. At operation, a liver biopsy and gallbladder bile were obtained. Twenty-eight untreated gallstone patients undergoing cholecystectomy served as controls. The study was carried out at a university hospital. RESULTS: Deoxycholic acid comprised 72 +/- 6% (mean +/- SEM) of total biliary bile acids in DCA-treated patients (n = 8), and 21 +/- 2% in the controls (n = 16; P < 0.001). Cholesterol saturation of gallbladder bile averaged 102% in both treated (n = 7) and untreated (n = 16) patients. Cholesterol 7alpha-hydroxylase and HMG CoA reductase activities and mRNA levels were not different between DCA-treated and untreated gallstone patients. The LDL receptor mRNA levels were similar in both groups of patients. Plasma levels of total cholesterol were lowered by 10% upon DCA treatment (P < 0.05). CONCLUSIONS: Treatment with DCA did not significantly affect mRNA levels and activity of hepatic cholesterol 7alpha-hydroxylase or HMG CoA reductase in patients with cholesterol gallstones. There was no effect on the saturation of gallbladder bile, Thus, the present study could not verify that the hydrophobicity of the bile acid pool is a major factor regulating human hepatic cholesterol 7alpha-hydroxylase activity. |
| Deoxygenation-induced alterations in sickle cell membrane cholesterol exchange Kavecansky, J., F. Schroeder, et al. (1995), Am J Physiol 269(5 Pt 1): C1105-11. Abstract: Changes in a membrane sterol exchange of sickle red blood cells (SS RBC) induced by deoxygenation were studied using the fluorescent cholesterol analogue dehydroergosterol (DHE). DHE uptake by SS RBC membrane was measured by the incubation of SS RBC with small unilamellar vesicles (SUV) containing DHE. Deoxygenation of SS RBC, but not normal RBC, increased the rate of DHE uptake. DHE membrane content after 5 h of incubation with SUV in the cell-to-SUV ratio of 1:1 (mol lipid) was 16.25 +/- 0.94 and 12.22 +/- 0.85% of total sterol for deoxygenated and oxygenated cells, respectively. Membrane spicules isolated from these deoxygenated SS RBC had three-fold higher DHE content, suggesting that the increased sterol exchange was localized to spicules. When isolated spicules were incubated with DHE-SUV directly, 91 +/- 3% of membrane sterol was rapidly exchanged, in contrast to intact RBC, in which a maximum of 33% of sterol could be exchanged. The results suggest that spicule formation in SS RBC alters membrane cholesterol structure, such that a domain of cholesterol that is normally nonexchangeable becomes readily exchangeable with exogenous sterol. |
| Dependence on dietary cholesterol for n-3 polyunsaturated fatty acid-induced changes in plasma cholesterol in the Syrian hamster Surette, M. E., J. Whelan, et al. (1992), J Lipid Res 33(2): 263-71. Abstract: Male Syrian hamsters consumed diets containing incremental increases in dietary n-3 fatty acids from fish oil with either low (0.015% w/w) or moderate (0.1% w/w) dietary cholesterol content. Animals consuming diets containing moderate cholesterol, but not animals consuming diets containing low cholesterol, had increased plasma very low (VLDL)- and low density lipoprotein (LDL)-cholesterol levels with increasing fish oil consumption. The plasma concentration of high density lipoprotein (HDL)-cholesterol decreased by 43 and 32% with the consumption of the highest fish oil diets in the low and moderate dietary cholesterol groups, respectively. Hepatic LDL-receptor binding activity did not change with the consumption of low cholesterol diets, but gradually decreased with fish oil consumption in animals consuming the moderate cholesterol diets. Hepatic LDL-receptor binding and plasma LDL-cholesterol levels of the different dietary fish oil groups were highly correlated (r = -0.91). Fish oil consumption also caused an increase in hepatic free cholesterol but a decreased cholesteryl ester content. Therefore, in the Syrian hamster, the consumption of n-3 fatty acids increases LDL-cholesterol levels which can be partially explained by decreased hepatic LDL-receptor binding and this response to dietary n-3 fatty acids is dependent on the dietary cholesterol content. However, the effects of dietary n-3 fatty acids on HDL-cholesterol are independent of dietary cholesterol content. |
| Depleting cell cholesterol alters calcium-induced assembly of tight junctions by monolayers of MDCK cells Lynch, R. D., L. J. Tkachuk, et al. (1993), Eur J Cell Biol 60(1): 21-30. Abstract: A role for lipids in the formation of tight junctions (TJ) has been proposed. Attempts to relate changes in whole cell phospholipid composition to the formation of TJs, however, have yielded equivocal results. The object in the present study was to relate changes in TJ of MDCK cells more specifically to alterations in plasma membrane lipids. Cholesterol, which resides primarily in the plasma membrane, was reduced by 25% after incubation of cell monolayers for 24 h in a low Ca2+ medium supplemented with (1-2 microM) Lovastatin, an inhibitor of hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase. This was associated with a halving of the time required for Ca2+ to induce TJ formation as monitored by transepithelial electrical resistance (TER). 3HMannitol flux, and morphometric measurements made on freeze fracture replicas confirm that the effects on TER reflect changes in the characteristics of the paracellular pathway. Peak and steady state values of TER were also elevated over control values. The changes in cholesterol content and the time course for TJ assembly were apparent at levels of Lovastatin which do not affect prenylation of proteins, and were prevented if 5 mM mevalonate was present along with Lovastatin. Paradoxically, despite a decrease of approximately 1/3 in the Ca concentration required to yield maximum rates of TJ assembly, 45Ca2+ uptake was actually reduced after cholesterol depletion. The data suggest that cholesterol may modulate the properties of membrane proteins and/or phospholipids which interact with Ca2+, possibly on the exoplasmic leaflet, during TJ assembly. |
| Depletion of Caco-2 cell cholesterol disrupts barrier function by altering the detergent solubility and distribution of specific tight-junction proteins Lambert, D., C. A. O'Neill, et al. (2005), Biochem J 387(Pt 2): 553-60. Abstract: In the present study, we have investigated the role of cholesterol in maintaining the barrier properties of the model intestinal cell line Caco-2. We have extracted membrane cholesterol using methyl-beta-cyclodextrin and demonstrated that maximally, methyl-beta-cyclodextrin lowered cell cholesterol levels by 40-45%. Depletion of cell cholesterol was accompanied by an 80-90% decrease in monolayer transepithelial electrical resistance and a significant increase in the paracellular permeability of dextrans of 4, 10 and 40 kDa. The increase in dextran permeability was most pronounced for the two lower molecular mass species. In addition to the decline in the barrier properties of the monolayers, extraction of cell cholesterol produced an increase in the Triton X-100 solubility of claudin 3, claudin 4 and occludin, and the loss of all three proteins from the plasma membrane (tight junctions). In contrast, removal of cholesterol had no detectable influence on the detergent solubility or morphological distribution of claudin 1. These results indicate that membrane cholesterol is a critical factor in maintaining the barrier property of epithelial monolayers. More specifically, cholesterol appears to stabilize the association of certain proteins with the tight junctions. |
| Depletion of cellular cholesterol and lipid rafts increases shedding of CD30 von Tresckow, B., K. J. Kallen, et al. (2004), J Immunol 172(7): 4324-31. Abstract: CD30, a lymphoid activation marker, is shed into the cell environment after endoproteolytic cleavage of its ectodomain. Soluble (s)CD30 is able to suppress the Th1-type immune response. Because high serum levels of sCD30 and cholesterol-lowering drugs seem to be beneficial in some Th1-type autoimmune diseases, we focused on a link between CD30 shedding and the amount of cellular cholesterol. Cholesterol depletion of human Hodgkin lymphoma- and non-Hodgkin lymphoma-derived cell lines by methyl-beta-cyclodextrin led to a down-regulation of membrane-bound CD30 and increased release of sCD30. Additionally, the cholesterol-interfering drugs lovastatin, cholesterol oxidase, and filipin increased CD30 shedding. Both the down-regulation of membrane-anchored CD30 and the release of sCD30 were dependent on metalloproteinases. Using specific inhibitors, we detected TNF-alpha converting enzyme (TACE) as the leading enzyme responsible for cholesterol-dependent CD30 shedding. A Triton X-100-based method for lipid raft isolation revealed that CD30 was partially present in lipid rafts, whereas TACE was localized in the nonraft fractions. Disintegration of lipid rafts by cholesterol depletion might therefore lead to dynamic interactions of CD30 with TACE, resulting in enhanced shedding of CD30. Our results suggest a possible role of cholesterol-dependent shedding of CD30 in the pathogenesis of immune diseases. |
| Depletion of cholesterol for signal transduction from endoplasmic reticulum to the cell nucleus--the proteolytic cleavage of transcription factors from the ER membranes Wieczorek, B. and J. Gniot-Szulzycka (2002), Postepy Biochem 48(3): 200-7. |
| Depletion of membrane cholesterol causes ligand-independent activation of Fas and apoptosis Gniadecki, R. (2004), Biochem Biophys Res Commun 320(1): 165-9. Abstract: Fas is a member of the tumour necrosis factor receptor superfamily. Fas-mediated apoptosis is an essential mechanism protecting against skin cancer. Activation of Fas by specific ligand or agonistic antibodies leads to the formation of a membrane associated death-inducing signalling complex comprising aggregates of Fas, the Fas-associated death domain protein (FADD), and caspase-8. It has recently been suggested that activity of Fas is not only regulated by its cognate ligand but also by the association of this receptor with cholesterol-enriched lipid domains in the plasma membrane (lipid rafts). We report here that disruption of lipid rafts by cholesterol-depleting compounds (methyl-beta-cyclodextrin, filipin III, cholesterol oxidase, and mevastatin) leads to a spontaneous clustering of Fas in the non-raft compartment of the plasma membrane, formation of Fas-FADD complexes, activation of caspase-8, and apoptosis. We propose that in some cell types exclusion of Fas from lipid rafts leads to the spontaneous, ligand-independent activation of this death receptor, a mechanism that can potentially be utilized in anticancer therapy. |
| Depletion of plasma membrane cholesterol dampens hydrostatic pressure and shear stress-induced mechanotransduction pathways in osteoblast cultures Ferraro, J. T., M. Daneshmand, et al. (2004), Am J Physiol Cell Physiol 286(4): C831-9. Abstract: The preferential association of cholesterol and sphingolipids within plasma membranes forms organized compartments termed lipid rafts. Addition of caveolin proteins to this lipid milieu induces the formation of specialized invaginated plasma membrane structures called caveolae. Both lipid rafts and caveolae are purported to function in vesicular transport and cell signaling. We and others have shown that disassembly of rafts and caveolae through depletion of plasma membrane cholesterol mitigates mechanotransduction processes in endothelial cells. Because osteoblasts are subjected to fluid-mechanical forces, we hypothesize that cholesterol-rich plasma membrane microdomains also serve the mechanotransduction process in this cell type. Cultured human fetal osteoblasts were subjected to either sustained hydrostatic pressure or laminar shear stress using a pressure column or parallel-plate apparatus, respectively. We found that sustained hydrostatic pressure induced protein tyrosine phosphorylation, activation of extracellular signal-regulated kinase (ERK)1/2, and enhanced expression of c-fos in both time- and magnitude-dependent manners. Similar responses were observed in cells subjected to laminar shear stress. Both sustained hydrostatic pressure- and shear stress-induced signaling were significantly reduced in osteoblasts pre-exposed to either filipin or methyl-beta-cyclodextrin. These mechanotransduction responses were restored on reconstitution of lipid rafts and caveolae, which suggests that cholesterol-rich plasma membrane microdomains participate in the mechanotransduction process in osteoblasts. In addition, mechanical force-induced phosphoproteins were localized within caveolin-containing membranes. These data support the concept that lipid rafts and caveolae serve a general function as cell surface mechanotransduction sites within the plasma membrane. |
| Depletion of pre beta 1LpA1 and LpA4 particles by mast cell chymase reduces cholesterol efflux from macrophage foam cells induced by plasma Lee, M., A. von Eckardstein, et al. (1999), Arterioscler Thromb Vasc Biol 19(4): 1066-74. Abstract: Exposure of the LpA1-containing particles present in HDL3 and plasma to a minimal degree of proteolysis by the neutral protease chymase from exocytosed rat mast cell granules (granule remnants) leads to a reduction in the high-affinity component of cholesterol efflux from macrophage foam cells. In this study, we demonstrate for the first time, a role for mast cell chymase in the depletion of the lipid-poor minor components of HDL that are specifically involved in reverse cholesterol transport as initial acceptors of cellular cholesterol. Thus, addition of proteolytically active granule remnants or human skin chymase to cholesterol-loaded macrophages of mouse or human origin incubated with human apoA1, ie, a system in which prebeta1LpA1 is generated, resulted in a sharp reduction in the high-affinity cholesterol efflux promoted by apoA1. As determined by nondenaturing 2-dimensional polyacrylamide gradient gel electrophoresis, the granule remnants effectively depleted the prebeta1LpA1, but not the alphaLpA1, in HDL3 and in plasma during incubation at 37 degrees C for <1 hour. Incubation of plasma with granule remnants for 1 hour also led to near disappearance of the LpA4-1 and LpA4-2 particles, but did not affect the distribution of the apoA2-containing lipoproteins present in the plasma. We conclude that the reduced ability of granule remnant-treated HDL3 and granule remnant-treated plasma to induce cholesterol efflux from macrophage foam cells is caused by selective depletion by mast cell chymase of quantitatively minor A1- and A4-containing subpopulations of HDL. Because these particles, ie, prebeta1LpA1 and LpA4, are efficient acceptors of cholesterol from cell surfaces, their depletion by mast cells may block the initiation of reverse cholesterol transport in vivo and thereby favor foam cell formation in the arterial intima, the site of atherogenesis. |
| Depletion of rafts in late endocytic membranes is controlled by NPC1-dependent recycling of cholesterol to the plasma membrane Lusa, S., T. S. Blom, et al. (2001), J Cell Sci 114(Pt 10): 1893-900. Abstract: In mammalian cells, cholesterol is thought to associate with sphingolipids to form lateral membrane domains termed rafts. Increasing evidence suggests that rafts regulate protein interactions, for example, during signalling, intracellular transport and host-pathogen interactions. Rafts are present in cholesterol-sphingolipid-enriched membranes, including early and recycling endosomes, but whether rafts are found in late endocytic organelles has not been analyzed. In this study, we analyzed the association of cholesterol and late endosomal proteins with low-density detergent-resistant membranes (DRMs) in normal cells and in cells with lysosomal cholesterol-sphingolipid accumulation. In normal cells, the majority of (3)Hcholesterol released from (3)Hcholesterol ester-LDL associated with detergent-soluble membranes, was rapidly transported to the plasma membrane and became increasingly insoluble with time. In Niemann-Pick C1 (NPC1) protein-deficient lipidosis cells, the association of LDL-cholesterol with DRMs was enhanced and its transport to the plasma membrane was inhibited. In addition, the NPC1 protein was normally recovered in detergent-soluble membranes and its association with DRMs was enhanced by lysosomal cholesterol loading. Moreover, lysosomal cholesterol deposition was kinetically paralleled by the sequestration of sphingolipids and formation of multilamellar bodies in late endocytic organelles. These results suggest that late endocytic organelles are normally raft-poor and that endocytosed LDL-cholesterol is efficiently recycled to the plasma membrane in an NPC1-dependent process. The cholesterol-sphingolipid accumulation characteristic to NPC disease, and potentially to other sphingolipidoses, causes an overcrowding of rafts forming lamellar bodies in the degradative compartments. |
| Depletion of Schistosoma mansoni lung-stage schistosomula cholesterol by methyl-beta-cyclodextrin dramatically increases specific antibody binding to surface membrane antigens El Ridi, R., H. Tallima, et al. (2004), J Parasitol 90(4): 727-32. Abstract: Schistosoma mansoni lung-stage larvae appear to not bind antibodies from radiation vaccine or infection sera in the membrane immunofluorescence test. However, treatment of ex vivo lung-stage schistosomula with methyl-beta-cyclodextrin, a hydrophobic oligosaccharide that specifically extracts cholesterol from plasma membranes, induced readily detectable binding of specific antibodies in a concentration- and time-dependent manner. Surface membrane antigen binding of specific antibodies was also conclusively demonstrated by quantitative absorption of anti-schistosome sera with intact ex vivo larvae. These data together suggest that confinement of lung-stage schistosomula surface membrane antigens in cholesterol-rich sites allows only monovalent antibody binding, which can be detected by absorption and not by direct serology. |
| Depressed albumin and high-density lipoprotein cholesterol: signposts along the final common pathway of frailty Hazzard, W. R. (2001), J Am Geriatr Soc 49(9): 1253-4. |
| Depressed serum high density lipoprotein cholesterol levels in veterans with spinal cord injury Bauman, W. A., A. M. Spungen, et al. (1992), Paraplegia 30(10): 697-703. Abstract: Cardiovascular diseases are the most frequent cause of death among persons with spinal cord injury (SCI), and these diseases are reported to occur prematurely in the disabled compared to the able bodied population. The mechanism of accelerated coronary heart disease (CHD) in persons with SCI may be partially explicable on the basis of the lipoprotein profile. We performed fasting lipoprotein determinations on 100 veterans with SCI, 50 with paraplegia and 50 with quadriplegia, and 50 veteran controls. The mean age of the subjects with SCI was 47.8 +/- 1.4 years with a duration of injury of 16.3 +/- 1.2 years. The mean serum high-density lipoprotein (HDL) cholesterol was depressed in subjects with paraplegia or quadriplegia compared to controls (37 +/- 1 or 40 +/- 1 versus 48 +/- 2 mg/dL, p < 0.0001). Although serum total cholesterol was lower (p < 0.01) in subjects with SCI than in controls, there was no significant difference in mean serum low-density lipoprotein (LDL) cholesterol. Thirty-seven percent of subjects with SCI have serum HDL cholesterol levels less than 35 mg/dL with no significant difference in lipoprotein distribution between high and low cord lesions. Eighteen percent of individuals with SCI have an absolute elevation of LDL cholesterol (greater than 160 mg/dL). About 40% of those with SCI and LDL cholesterol levels between 130 and 160 mg/dL also have serum HDL cholesterol values below 35 mg/dL, all of whom would have their serum HDL cholesterol level undetected if lipoprotein profiles were performed according to present recommendations--that is, only if the serum total cholesterol is elevated.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Depression in cardiac contractile force induced by cholesterol Shah, K. R., F. Kolar, et al. (1990), Cardioscience 1(4): 255-9. Abstract: Cholesterol, combined with albumin, induced rapid functional changes in the isolated perfused rat heart. Under constant perfusion pressure, the decline in contractile force and the rate of development of force due to cholesterol was accompanied by an increase in resting tension and a decrease in coronary flow. Such effects were not produced by albumin alone. Depression in contractile force and increase in resting tension were also evident when coronary flow was kept constant; these effect of cholesterol were dependent on time and dose. The findings support the view that cholesterol may affect cardiac function independently of the atherosclerotic lesion in the hypercholesterolemic state. |
| Depression of plasma cholesterol in men by consumption of baked products containing soy protein Potter, S. M., R. M. Bakhit, et al. (1993), Am J Clin Nutr 58(4): 501-6. Abstract: The effects of soy-protein consumption with and without soy fiber on plasma lipids in 26 mildly hypercholesterolemic men were studied. Four, 4-wk dietary treatments included 50 g protein and 20 g dietary fiber from soy flour (SF), isolated soy protein/soy cotyledon fiber (ISP/SCF), ISP/cellulose (ISP/C), or nonfat dry milk/C (NFDM/C) in conjunction with a low-fat, low-cholesterol diet. Plasma total cholesterol (TC) concentrations were lowest for both ISP dietary treatments compared with baseline (P < 0.05) and NFDM/C (P < 0.01). SF also led to lower TC compared with NFDM/C (P < 0.05). LDL-cholesterol values were lowest for both ISP treatments compared with NFDM/C (P < 0.01), but lower compared with baseline only with ISP/SCF (P < 0.05). Apolipoprotein B was lowest when ISP/C was fed, compared with baseline, SF, and NFDM (P < 0.05). HDL-cholesterol and total triglycerides (TG) were not affected. Results indicate that 50 g ISP is effective in lowering TC, LDL-C, and apolipoprotein B while maintaining HDL concentrations in mildly hypercholesterolemic men. |
| Desialylation of human apolipoprotein E decreases its binding to human high-density lipoprotein and its ability to deliver esterified cholesterol to the liver Marmillot, P., M. N. Rao, et al. (1999), Metabolism 48(9): 1184-92. Abstract: Apolipoprotein E (apoE) plays a significant role in the delivery of high-density lipoprotein (HDL) cholesterol to the liver via the apoB/E receptor. The roles of the apoE sialylation status in its association with HDL and in the reverse cholesterol transport (RCT) function of HDL have not been well defined. Furthermore, long-term ethanol treatment impairs apoE sialylation and leads to its decreased content in HDL. Therefore, we investigated the association of either sialo apoE (SapoE) or desialo apoE (DSapoE) with HDL and its effect on the RCT function of HDL. The dextran sulfate precipitation method showed that 125IDSapoE binding to HDL was 27.3% (P <.02) to 35.5% (P <.001) lower versus 125ISapoE. Scatchard analysis of the specific binding data showed that 125ISapoE had 11.2 times more affinity for HDL than 125IDSapoE based on size-exclusion chromatography (Kd = 89.7 v 1,010 nmol/L). Similarly, 1251HDL had 4.5 times more affinity for SapoE compared with DSapoE based on solid-phase binding (Kd = 21.9 v 104.4 nmol/L). Furthermore, esterified cholesterol uptake from reconstituted HDL particles (rHDLs) by HepG2 cells increased over basal uptake up to 153% when rHDLs contained SapoE, versus only 37% with DSapoE. Enzymatic resialylation of DSapoE completely restored its HDL-binding and RCT properties, identical to those of SapoE. It is therefore concluded that desialylation of apoE decreases its binding to plasma HDL, leading to an impaired RCT function. |
| Design and baseline characteristics of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) study Amarenco, P., J. Bogousslavsky, et al. (2003), Cerebrovasc Dis 16(4): 389-95. Abstract: Evidence suggests that statin therapy reduces the risk of stroke in patients with coronary heart disease (CHD), but its benefit for patients with cerebrovascular disease and no history of CHD remains uncertain. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study is a prospective, multi-centre, double-blind, randomised, placebo-controlled trial designed to evaluate the effects of atorvastatin 80 mg/day in patients who previously experienced a stroke or transient ischaemic attack, but who have no known CHD. A total of 4732 patients have been enrolled, and the data collection phase of the study is expected to be completed by October 2004. SPARCL is the first study primarily designed to prospectively evaluate the effect of statin treatment in secondary stroke prevention. |