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‣ Estudos estruturais da proteína PelD de Pseudomonas aeruginosa: um receptor de c-di-GMP responsável pela produção de exopolissacarídeos e formação de biofilmes; Structural studies of Pseudomonas aeruginosa PelD protein: a receptor c-di-GMP responsible for the production of exopolysaccharides and biofilm formation

Silva, Sumária Sousa e
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 06/02/2013 Português
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Os microrganismos podem apresentar-se tanto em forma de vida livre como aderidos a uma superfície ou interface ar-líquido, formando comunidades complexas e dinâmicas conhecidas como biofilmes. Nos últimos anos, com o avanço das pesquisas em nível molecular, foi identificado que a maioria das bactérias utilizam guanosina monofosfato (3´-5´)-cíclica dimérica (c-di-GMP) como um segundo mensageiro. De forma geral, essa molécula controla a sinalização celular, virulência, comunicação entre células e a expressão de proteínas relacionadas com o fenótipo de biofilmes, em resposta à sua concentração intracelular. Sua síntese e degradação são controladas respectivamente por diguanilto ciclases (DGCs) contendo domínio GGDEF e fosfodiesterases (PDEs) que possuem os domínios EAL ou HD-GYP. Em Pseudomonas aeruginosa (PA14) foi identificada uma nova classe de receptor específico para c-di-GMP, a proteína transmembranar PelD, cuja porção citoplasmática contém os domínios GAF e GGDEF degenerado. Sua modulação através desse dinucleotídeo controla a produção de exopolissacarídeos pelos componentes do conservado operon pel e influencia diretamente na capacidade de formação de biofilmes. Devido à escassez de dados a respeito dos eventos moleculares do mecanismo de sinalização mediado por c-di-GMP...

‣ Influences of alpha-tocopherol on cholesterol metabolism and fatty streak development in apolipoprotein E-deficient mice fed an atherogenic diet

Peluzio,M.C.G.; Homem,A.P.P.; Cesar,G.C.; Azevedo,G.S.; Amorim,R.; Cara,D.C.; Saliba,H.; Vieira,E.C.; Arantes,R.E.; Alvarez-Leite,J.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2001 Português
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Although the role of oxidized lipoproteins is well known in atherogenesis, the role of vitamin E supplementation is still controversial. There is also little information about cholesterol metabolism (hepatic concentration and fecal excretion) in the new models of atherosclerosis. In the present study, we evaluated the effect of moderate vitamin E supplementation on cholesterol metabolism and atherogenesis in apolipoprotein E (apo E)-deficient mice. Apo E-deficient mice were fed an atherogenic diet containing 40 or 400 mg/kg of alpha-tocopherol acetate for 6 weeks. Total cholesterol in serum and liver and 3-OH-alpha-sterols in feces, and fecal excretion of bile acids were determined and histological analyses of aortic lesion were performed. A vitamin E-rich diet did not affect body weight, food intake or serum cholesterol. Serum and hepatic concentrations of cholesterol as well as sterol concentration in feces were similar in both groups. However, when compared to controls, the alpha-tocopherol-treated mice showed a reduction of about 60% in the atherosclerotic lesions when both the sum of lesion areas and the average of the largest lesion area were considered. These results demonstrate that supplementation of moderate doses of alpha-tocopherol was able to slow atherogenesis in apo E-deficient mice and to reduce atherogenic lipoproteins without modifying the hepatic pool or fecal excretion of cholesterol and bile acids.

‣ Effect of Lactobacillus delbrueckii on cholesterol metabolism in germ-free mice and on atherogenesis in apolipoprotein E knock-out mice

Portugal,L.R.; Gonçalves,J.L.; Fernandes,L.R.; Silva,H.P.S.; Arantes,R.M.E.; Nicoli,J.R.; Vieira,L.Q.; Alvarez-Leite,J.I.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/05/2006 Português
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Elevated blood cholesterol is an important risk factor associated with atherosclerosis and coronary heart disease. Several studies have reported a decrease in serum cholesterol during the consumption of large doses of fermented dairy products or lactobacillus strains. The proposed mechanism for this effect is the removal or assimilation of intestinal cholesterol by the bacteria, reducing cholesterol absorption. Although this effect was demonstrated in vitro, its relevance in vivo is still controversial. Furthermore, few studies have investigated the role of lactobacilli in atherogenesis. The aim of the present study was to determine the effect of Lactobacillus delbrueckii on cholesterol metabolism in germ-free mice and the possible hypocholesterolemic and antiatherogenic action of these bacteria using atherosclerosis-prone apolipoprotein E (apo E) knock-out (KO) mice. For this purpose, Swiss/NIH germ-free mice were monoassociated with L. delbrueckii and fed a hypercholesterolemic diet for four weeks. In addition, apo E KO mice were fed a normal chow diet and treated with L. delbrueckii for 6 weeks. There was a reduction in cholesterol excretion in germ-free mice, which was not associated with changes in blood or liver cholesterol concentration. In apo E KO mice...

‣ Apolipoprotein (apo) E inhibits the capacity of monosodium urate crystals to stimulate neutrophils. Characterization of intraarticular apo E and demonstration of apo E binding to urate crystals in vivo.

Terkeltaub, R A; Dyer, C A; Martin, J; Curtiss, L K
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1991 Português
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Factors that modulate the ability of monosodium urate crystals to stimulate leukocytes could regulate gouty inflammation. Lipoproteins that bear apo B-100 and apo E bind to urate crystals and suppress crystal-neutrophil interaction. In this study, we observed that urate crystals, coated with apo E of monocyte origin, had a diminished ability to stimulate neutrophils. Apo E was also detected on the surface of urate crystals recovered from gout patients. Thus, we analyzed apo E in noninflammatory synovial fluid, and found it to be associated with particles of heterogeneous size and of predominantly alpha and pre-beta electrophoretic mobility. Local articular synthesis of at least a portion of synovial fluid apo E was suggested because (a) the synovial fluid/plasma concentration ratio of apo E was significantly higher than that for both apo B and apo A-I, which are not widely synthesized by extrahepatic tissues, (b) cultured rheumatoid synovial cells in first passage secreted apo E, (c) a portion of synovial fluid apo E was heavily sialylated. We conclude that synovial fluids contain apo E that appears partly of local origin. Apo E binds to urate crystals and could modulate gouty inflammation.

‣ Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice.

Pászty, C; Maeda, N; Verstuyft, J; Rubin, E M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1994 Português
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Apolipoprotein E (apo E)-deficient mice are severely hypercholesterolemic and develop advanced atheromas independent of diet. The C57BL/6 strain differs from most inbred strains by having lower HDL concentrations and a high risk of developing early atherosclerotic lesions when fed an atherogenic diet. The relative HDL deficiency and atherosclerosis susceptibility of the C57BL/6 strain are corrected with the expression of a human apolipoprotein AI (apo AI) transgene in this genetic background. To examine if increases in apo AI and HDL are also effective in minimizing apo E deficiency--induced atherosclerosis, we introduced the human apo AI transgene into the hypercholesterolemic apo E knockout background. Similar elevations of total plasma cholesterol occurred in both the apo E knockout and apo E knockout mice also expressing the human apo AI transgene. The latter animals, however, also showed a two- to threefold increase in HDL and a sixfold decrease in susceptibility to atherosclerosis. This study demonstrates that elevating the concentration of apo AI reduces atherosclerosis in apo E deficient-mice and suggests that elevation of apo AI and HDL may prove to be a useful approach for treating unrelated causes of heightened atherosclerosis susceptibility.

‣ Isoprotein specificity in the hepatic uptake of apolipoprotein E and the pathogenesis of familial dysbetalipoproteinemia.

Havel, R J; Chao, Y; Windler, E E; Kotite, L; Guo, L S
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1980 Português
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The uptake and catabolism of lamellar complexes of rat 125I-labeled apolipoprotein (apo) E with egg lecithin were increased severalfold in perfused livers of rats given large amounts of 17 alpha-ethynylestradiol for 5 days. Estrogen-stimulated uptake of lamellar complexes of human apo E that contained all of the major normally occurring "isoforms" of the protein (apo E-1, E-2, E-3, and E-4) was comparable to that of rat apo E. By contrast, uptake of complexes containing apo E from individuals with familial dysbetalipoproteinemia (dys beta LP; characterized by a lack of apo E-3 and E-4) was stimualted to a much smaller extent. With complexes containing individual isoforms of human apo E, it was shown that estrogen-stimulated hepatic uptake was largely confined to apo E-3 and E-4; uptake of apo E-2 from normolipoproteinemic or dys beta LP individuals, or of apo E-1 from the latter, was stimulated little or not at all. When considered in the light of available information about the hepatic uptake of lipoproteins and the metabolic defect in familial dys beta LP, these results are consistent with the following hypothesis: (i) apo E comprises an essential component of the site for normal recognition of remnants of triglyceride-rich lipoproteins by a specific hepatic receptor; (ii) accumulation of remnant lipoproteins in familial dys beta LP is caused by lack of apo E-3 and E-4...

‣ Two independent lipoprotein receptors on hepatic membranes of dog, swine, and man. Apo-B,E and apo-E receptors.

Mahley, R W; Hui, D Y; Innerarity, T L; Weisgraber, K H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1981 Português
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We have reported previously that canine livers possess two distinct lipoprotein receptors, an apoprotein (apo)-B,E receptor capable of binding the apo-B-containing low density lipoproteins (LDL) and the apo-E-containing cholesterol-induced high density lipoproteins (HDLc), and an apo-E receptor capable of binding apo-E HDLc but not LDL. Both the apo-B,E and apo-E receptors were found on the liver membranes obtained from immature growing dogs, but only the apo-E receptors were detected on th hepatic membranes of adult dogs. In this study, the expression of the apo-B,E receptors, as determined by canine LDL binding to the hepatic membranes, was found to be highly dependent on the age of the dog and decreased linearly with increasing age. Approximately 30 ng of LDL protein per milligram of membrane protein were bound via the apo-B,E receptors to the hepatic membranes of 7- to 8-wk-old immature dogs as compared with no detectable LDL binding in the hepatic membranes of adult dogs (greater than 1--1.5 yr of age). Results obtained by in vivo turnover studies of canine 125I-LDL correlated with the in vitro findings. In addition to a decrease in the expression of the hepatic apo-B,E receptors with age, these receptors were regulated, i.e....

‣ Rate and equilibrium constants for binding of apo-E HDLc (a cholesterol-induced lipoprotein) and low density lipoproteins to human fibroblasts: Evidence for multiple receptor binding of apo-E HDLc

Pitas, R. E.; Innerarity, T. L.; Arnold, K. S.; Mahley, R. W.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/1979 Português
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Competitive binding assays have demonstrated that a cholesterol-induced canine lipoprotein containing only the E apoprotein (apo-E HDLc) binds to the same cell surface receptors of human fibroblasts as human low density lipoproteins (LDL). However, the apo-E HDLc have a much greater binding activity than LDL. Equilibrium and kinetic binding studies were conducted at 4°C to determine the mechanism for this enhanced receptor binding activity. Based on the data, the binding of both LDL and apo-E HDLc appears to be a simple bimolecular receptor interaction, and no heterogeneity of binding sites or cooperative effects among the receptor sites were observed. Equilibrium dissociation constants determined by Scatchard analysis of the equilibrium binding data for apo-E HDLc (Kd = 0.12 × 10-9 M) and LDL (Kd = 2.8 × 10-9 M) revealed a 23-fold greater affinity of HDLc for the receptors. Association and dissociation rate constants for the lipoprotein-receptor complex were determined from the time course of binding at various lipoprotein concentrations. The equilibrium dissociation constants calculated from these kinetic data confirmed that apo-E HDLc had a much higher affinity for the receptor than LDL. Furthermore, the kinetic studies indicated that apo-E HDLc bound more rapidly than LDL with rates of association of 18.0 × 104 and 5.5 × 104 M-1 sec-1...

‣ Role of apolipoprotein E in the lipolytic conversion of beta-very low density lipoproteins to low density lipoproteins in type III hyperlipoproteinemia.

Ehnholm, C; Mahley, R W; Chappell, D A; Weisgraber, K H; Ludwig, E; Witztum, J L
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1984 Português
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The beta-very low density lipoproteins (beta-VLDL) that accumulate in type III hyperlipoproteinemic subjects can be divided into two fractions (fraction I and fraction II), which differ in size, lipid composition, and the type of apolipoprotein B (apo-B) present in the particles. The apo-B48-containing particles (fraction I) are of intestinal origin, while apo-B100-containing particles (fraction II) are derived from the liver. Both fractions contain a defective form of apo-E referred to as apo-E2. Intravenous infusion of heparin into two subjects with type III hyperlipoproteinemia resulted in the complete removal of fraction II particles from density less than 1.006 g/ml, while fraction I particles remained at this density. In vitro studies confirmed that fraction I particles did not change density when subjected to hydrolysis with lipoprotein lipase, while fraction II particles shifted to the intermediate density lipoprotein range (approximately equal to 1.02 g/ml). When the beta-VLDL were hydrolyzed by lipoprotein lipase in the presence of density greater than 1.21 g/ml lipoprotein-deficient plasma, the addition of normal apo-E (apo-E3), but not apo-E2, resulted in a shift of fraction II particles to the low density lipoprotein (LDL) range (approximately equal to 1.05 g/ml). Fraction I particles did not undergo a shift to this higher density...

‣ Apo E structure determines VLDL clearance and atherosclerosis risk in mice

Knouff, Christopher; Hinsdale, Myron E.; Mezdour, Hafid; Altenburg, Michael K.; Watanabe, Masahiko; Quarfordt, Steven H.; Sullivan, Patrick M.; Maeda, Nobuyo
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
Publicado em 01/06/1999 Português
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We have generated mice expressing the human apo E4 isoform in place of the endogenous murine apo E protein and have compared them with mice expressing the human apo E3 isoform. Plasma lipid and apolipoprotein levels in the mice expressing only the apo E4 isoform (4/4) did not differ significantly from those in mice with the apo E3 isoform (3/3) on chow and were equally elevated in response to increased lipid and cholesterol in their diet. However, on all diets tested, the 4/4 mice had approximately twice the amount of cholesterol, apo E, and apo B-48 in their VLDL as did 3/3 mice. The 4/4 VLDL competed with human LDL for binding to the human LDL receptor slightly better than 3/3 VLDL, but the VLDL clearance rate in 4/4 mice was half that in 3/3 mice. On an atherogenic diet, there was a trend toward greater atherosclerotic plaque size in 4/4 mice compared with 3/3 mice. These data, together with our earlier observations in wild-type and human APOE*2-replacement mice, demonstrate a direct and highly significant correlation between VLDL clearance rate and mean atherosclerotic plaque size. Therefore, differences solely in apo E protein structure are sufficient to cause alterations in VLDL residence time and atherosclerosis risk in mice.

‣ Apo A-I inhibits foam cell formation in apo E–deficient mice after monocyte adherence to endothelium

Dansky, Hayes M.; Charlton, Sherri A.; Barlow, Courtenay B.; Tamminen, Minna; Smith, Jonathan D.; Frank, Joy S.; Breslow, Jan L.
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
Publicado em 01/07/1999 Português
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We have previously shown that expression of the human apo A-I transgene on the apo E–deficient background increases HDL cholesterol and greatly diminishes fatty streak lesion formation. To examine the mechanism, prelesional events in atherosclerotic plaque development were examined in 6- to 8-week-old apo E–deficient and apo E–deficient/human apo A-I transgenic mice. A quantitative assessment of subendothelial lipid deposition by freeze-fracture and deep-etch electron microscopy indicated that elevated apo A-I did not affect the distribution or amount of aortic arch subendothelial lipid deposits. Immunohistochemical staining for VCAM-1 demonstrated similar expression on endothelial cells at prelesional aortic branch sites from both apo E–deficient and apo E–deficient/human apo A-I transgenic mice. Transmission electron microscopy revealed monocytes bound to the aortic arch in mice of both genotypes, and immunohistochemical staining demonstrated that the area occupied by bound mononuclear cells was unchanged. Serum paraoxonase and aryl esterase activity did not differ between apo E–deficient and apo E–deficient/human apo A-I transgenic mice. These data suggest that increases in apo A-I and HDL cholesterol inhibit foam cell formation in apo E–deficient/human apo A-I transgenic mice at a stage following lipid deposition...

‣ Roles of apolipoproteins B and E in the cellular binding of very low density lipoproteins.

Krul, E S; Tikkanen, M J; Cole, T G; Davie, J M; Schonfeld, G
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1985 Português
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Apoproteins B and E both interact with cellular low density lipoprotein (LDL) apolipoprotein B and E (apo B,E)-receptors, and very low density lipoproteins (VLDL) contain both apo B and apo E. Our aim was to study the relative importance of apo B and apo E in the binding of VLDL subfractions to cells. Two monoclonal anti-LDL-apo B antibodies (464B1B3 and 464B1B6, 2a and 2b, respectively) and two anti-apo E antibodies (1506 A1.4 and 1907 F6.4) were used to inhibit lipoprotein-cell interactions. In confirmation of previous findings, the binding and degradation of 125I-LDL by human fibroblasts were inhibited approximately 90% by antibodies 2a or 2b or the antigen-binding fragments of 2a, whereas the cellular processing of 125I-VLDL3 (Sf20-60), 125I-VLDL2 (Sf60-120), and 125I-VLDL1 (Sf greater than 120) were inhibited by only approximately 50%, approximately 25%, and less than 10%, respectively. The VLDL1-3 and LDL-dependent intracellular esterification of cholesterol with [3H]oleate were inhibited to a similar extent. Other monoclonal anti-human apo B antibodies inhibited lipoprotein-cell interactions much less effectively and nonimmune IgG isolated from mouse serum did not inhibit at all. 20-fold excesses of LDL produced about the same patterns of inhibition of degradation of 125I-VLDL1-3 and LDL by cells as did antibodies 2a and 2b...

‣ Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system.

Boyles, J K; Pitas, R E; Wilson, E; Mahley, R W; Taylor, J M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1985 Português
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The plasma protein apolipoprotein (apo) E is an important determinant of lipid transport and metabolism in mammals. In the present study, immunocytochemistry has been used to identify apo E in specific cells of the central and peripheral nervous systems of the rat. Light microscopic examination revealed that all astrocytes, including specialized astrocytic cells (Bergmann glia of the cerebellum, tanycytes of the third ventricle, pituicytes of the neurohypophysis, and Müller cells of the retina), possessed significant concentrations of apo E. In all of the major subdivisions of the central nervous system, the perinuclear region of astrocytic cells, as well as their cell processes that end on basement membranes at either the pial surface or along blood vessels, were found to be rich in apo E. Extracellular apo E was present along many of these same surfaces. The impression that apo E is secreted by astrocytic cells was confirmed by electron microscopic immunocytochemical studies, which demonstrated the presence of apo E in the Golgi apparatus. Apo E was not present in neurons, oligodendroglia, microglia, ependymal cells, and choroidal cells. In the peripheral nervous system, apo E was present within the glia surrounding sensory and motor neurons; satellite cells of the dorsal root ganglia and superior cervical sympathetic ganglion as well as the enteric glia of the intestinal ganglia were reactive. Apo E was also present within the non-myelinating Schwann cells but not within the myelinating Schwann cells of peripheral nerves. These results suggest that apo E has an important...

‣ Impaired hepatic apolipoprotein B and E translation in streptozotocin diabetic rats.

Sparks, J D; Zolfaghari, R; Sparks, C E; Smith, H C; Fisher, E A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/1992 Português
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Studies of streptozotocin-induced diabetes in rats have demonstrated that hepatic apo B and apo E production are reduced. To determine if reductions are related to decreases in hepatic mRNAs, we performed blotting analysis of total liver RNA with rat apo B, apo E, and albumin cDNA probes. The expected reduction in albumin mRNA levels to 48% of control livers occurred in diabetic rat liver, while apo B and apo E mRNA levels were unchanged. The proportion of translational stop codon (BSTOP) mRNA averaged 43% of total in diabetic rats similar to control levels. Long-term labeling experiments using [35S]methionine in primary cultures of rat hepatocytes and specific immunoprecipitations demonstrated production of apo B and apo E, and albumin by hepatocytes from diabetic rats was reduced to 37%, 53%, and 23% of controls. Pulse-chase studies, together with mRNA analyses, suggest that reduced hepatic secretion of apo B and apo E in diabetics is primarily a result of impaired translation and not intracellular degradation. Ribosome transit studies directly confirmed the prolonged elongation rates for apo B and apo E mRNAs in hepatocytes derived from diabetic rats. This effect was more pronounced on apo BH (higher molecular weight) than on apo BL (lower molecular weight). Treatment of diabetic rats with insulin for 7 d led to normalization of hepatic albumin mRNA levels with no substantial change in apo E mRNA levels. In contrast...

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

Aalto-Setälä, K; Fisher, E A; Chen, X; Chajek-Shaul, T; Hayek, T; Zechner, R; Walsh, A; Ramakrishnan, R; Ginsberg, H N; Breslow, J L
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1992 Português
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Hypertriglyceridemia is common in the general population, but its mechanism is largely unknown. In previous work human apo CIII transgenic (HuCIIITg) mice were found to have elevated triglyceride levels. In this report, the mechanism for the hypertriglyceridemia was studied. Two different HuCIIITg mouse lines were used: a low expressor line with serum triglycerides of approximately 280 mg/dl, and a high expressor line with serum triglycerides of approximately 1,000 mg/dl. Elevated triglycerides were mainly in VLDL. VLDL particles were 1.5 times more triglyceride-rich in high expressor mice than in controls. The total amount of apo CIII (human and mouse) per VLDL particle was 2 and 2.5 times the normal amount in low and high expressors, respectively. Mouse apo E was decreased by 35 and 77% in low and high expressor mice, respectively. Under electron microscopy, VLDL particles from low and high expressor mice were found to have a larger mean diameter, 55.2 +/- 16.6 and 58.2 +/- 17.8 nm, respectively, compared with 51.0 +/- 13.4 nm from control mice. In in vivo studies, radiolabeled VLDL fractional catabolic rate (FCR) was reduced in low and high expressor mice to 2.58 and 0.77 pools/h, respectively, compared with 7.67 pools/h in controls...

‣ Hepatic apo E expression is required for remnant lipoprotein clearance in the absence of the low density lipoprotein receptor.

Linton, M F; Hasty, A H; Babaev, V R; Fazio, S
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/04/1998 Português
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According to the secretion-capture model of remnant lipoprotein clearance, apo E secreted by hepatocytes into the space of Disse serves to enrich the remnants with a ligand for receptor-mediated lipoprotein endocytosis. Current evidence supports a two-receptor model of lipoprotein removal, in which apo E-containing remnants bind either the low density lipoprotein receptor (LDLR) or the LDLR-related protein (LRP). Recently, we demonstrated that reconstitution of apo E(-/-) mice with apo E(+/+) marrow results in normalization of plasma lipoprotein levels, indicating that hepatic expression of apo E is not required for remnant clearance and calling into question the relevance of the secretion-capture mechanism. To dissect the relative contributions of LDLR and LRP to the cellular catabolism of remnant lipoproteins by the hepatocyte, bone marrow transplantation (BMT) was used to reconstitute macrophage expression of apo E in mice that were null for expression of both apo E and the LDLR. Reconstitution of macrophage apo E in apo E(-/-)/LDLR(-/-) mice had no effect on serum lipid and lipoprotein concentrations, although it produced plasma apo E levels up to 16-fold higher than in C57BL/6 controls. Immunocytochemistry of hepatic sections revealed abundant staining for apo E in the space of Disse...

‣ Substitution of the carboxyl-terminal domain of apo AI with apo AII sequences restores the potential of HDL to reduce the progression of atherosclerosis in apo E knockout mice.

Holvoet, P; Danloy, S; Deridder, E; Lox, M; Bernar, H; Dhoest, A; Collen, D
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/07/1998 Português
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HDL metabolism and atherosclerosis were studied in apo E knockout (KO) mice overexpressing human apo AI, a des- (190-243)-apo AI carboxyl-terminal deletion mutant of human apo AI or an apo AI-(1-189)-apo AII-(12-77) chimera in which the carboxyl-terminal domain of apo AI was substituted with the pair of helices of apo AII. HDL cholesterol levels ranked: apo AI/apo E KO approximately apo AI-(1-189)-apo AII- (12-77)/apo E KO > > des-(190-243)-apo AI/apo E KO > apo E KO mice. Progression of atherosclerosis ranked: apo E KO > des-(190-243)-apo AI/apo E KO > > apo AI-(1-189)- apo AII-(12-77)/apo E KO approximately apo AI/apo E KO mice. Whereas the total capacity to induce cholesterol efflux from lipid-loaded THP-1 macrophages was higher for HDL of mice overexpressing human apo AI or the apo AI/apo AII chimera, the fractional cholesterol efflux rate, expressed in percent cholesterol efflux/microg apolipoprotein/h, for HDL of these mice was similar to that for HDL of mice overexpressing the deletion mutant and for HDL of apo E KO mice. This study demonstrates that the tertiary structure of apo AI, e.g., the number and organization of its helices, and not its amino sequence is essential for protection against atherosclerosis because it determines HDL cholesterol levels and not cholesterol efflux. Amino acid sequences of apo AII...

‣ Simultaneous effects of the apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism.

Boerwinkle, E; Utermann, G
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1988 Português
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Human apolipoprotein (apo) E is polymorphic. We have investigated the effect of the apo-E polymorphism on quantitative plasma levels of apo E, apo B, and total cholesterol in a sample of 563 blood-bank donors from Marburg and Giessen, West Germany. The relative frequencies of the epsilon 2, epsilon 3, and epsilon 4 alleles are .063, .793, and .144, respectively. The average effects of the epsilon 2 allele are to raise apo-E levels by 0.95 mg/dl, lower apo B levels by 9.46 mg/dl, and lower total cholesterol levels by 14.2 mg/dl. The average effects of the epsilon 4 allele are to lower apo-E levels by 0.19 mg/dl, to raise apo-B levels by 4.92 mg/dl, and to raise total cholesterol levels by 7.09 mg/dl. The average effects of the epsilon 3 allele are near zero for all three phenotypes. The apo-E polymorphism accounts for 20% of the variability of plasma apo-E levels, 12% of the variability of plasma apo-B levels, and 4% of the variability of total plasma cholesterol levels. The inverse relationship between the genotype-specific average apo-E levels and both the genotype-specific average apo-B and cholesterol levels is offset by a positive relationship between apo-E levels and both apo-B and cholesterol levels within an apo-E genotype. The apo-E polymorphism also has a direct effect on the correlation between apo-E and total cholesterol levels. The implication of these results on multivariate genetic analyses of these phenotypes is discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

‣ CSF Apo-E levels associate with cognitive decline and MRI changes

Toledo, Jon B.; Da, Xiao; Weiner, Michael W.; Wolk, David A.; Xie, Sharon X.; Arnold, Steven E.; Davatzikos, Christos; Shaw, Leslie M.; Trojanowski, John Q.;
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for Alzheimer’s disease (AD) and it is thought to do so by modulating levels of the its product, apolipoprotein E (Apo-E), and regulating amyloid-β (Aβ) clearance. However, information on clinical and biomarker correlates of Apo-E proteins is scarce. We examined the relationship of cerebrospinal fluid (CSF) and plasma Apo-E protein levels, and APOE genotype to cognition and AD biomarker changes in 311 AD Neuroimaging Initiative (ADNI) subjects with CSF Apo-E measurements and 565 subjects with plasma Apo-E measurements. At baseline, higher CSF Apo-E levels were associated with higher total and phosphorylated CSF tau levels. CSF Apo-E levels were associated with longitudinal cognitive decline, MCI conversion to dementia, and grey matter atrophy rate in total tau/Aβ1–42 ratio and APOE genotype adjusted analyses. In analyses stratified by APOE genotype, our results were only significant in the group without the ε4 allele. Baseline CSF Apo-E levels did not predict longitudinal CSF Aβ or tau changes. Plasma Apo-E levels show a mild correlation with CSF Apo-E levels, but were not associated with longitudinal cognitive and MRI changes. Based on our analyses...

‣ Quercetin prevents left ventricular hypertrophy in the Apo E knockout mouse☆

Ulasova, Elena; Perez, Jessica; Hill, Bradford G.; Bradley, Wayne E.; Garber, David W.; Landar, Aimee; Barnes, Stephen; Prasain, Jeevan; Parks, Dale A.; Dell'Italia, Louis J.; Darley-Usmar, Victor M.
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em 16/07/2013 Português
Relevância na Pesquisa
57.301357%
Hypercholesterolemia is a risk factor for the development of hypertrophic cardiomyopathy. Nevertheless, there are few studies aimed at determining the effects of dietary compounds on early or mild cardiac hypertrophy associated with dyslipidemia. Here we describe left ventricular (LV) hypertrophy in 12 week-old Apo E−/− hypercholesterolemic mice. The LV end diastolic posterior wall thickness and overall LV mass were significantly increased in Apo E−/− mice compared with wild type (WT) controls. Fractional shortening, LV end diastolic diameter, and hemodynamic parameters were unchanged from WT mice. Oral low dose quercetin (QCN; 0.1 µmol QCN/kg body weight for 6 weeks) significantly reduced total cholesterol and very low density lipoprotein in the plasma of Apo E−/− mice. QCN treatment also significantly decreased LV posterior wall thickness and LV mass in Apo E−/− mice. Myocardial geometry and function were unaffected in WT mice by QCN treatment. These data suggest that dietary polyphenolic compounds such as QCN may be effective modulators of plasma cholesterol and could prevent maladaptive myocardial remodeling.