Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the expression of apolipoprotein E (ApoE) mRNA in the cerebella of control and experimental rabbits fed with a cholesterol-rich diet for 8 weeks. Cholesterol-treated rabbits show a dramatic increase in serum cholesterol levels; however, no significant variations in the expression level of cerebellar ApoE mRNA were found in comparison to control rabbits. In addition, no differences were observed between control and hypercholesterolemic rabbits in the in situ hybridization pattern of ApoE mRNA on cerebellar cortex sections. ApoE mRNA was localized in astroglial processes associated with Purkinje cell bodies and dendrites, granule cell clusters, blood vessels and nerve fibers of the white matter. No expression of ApoE mRNA was observed in Purkinje and granule cell neurons. Polarized light examination of cryostat cerebellar sections revealed the absence of cholesterol-rich microglia/macrophage cells induced by the hypercholesterolemia. In this way, neither reactive microglial cells nor perivascular phagocytes were found by ultrastructural analysis in hypercholesterolemic conditions. The pattern of glial fibrillary acidic protein of the astroglial cells of the cerebellar cortex as well as their nuclear size were unchanged following cholesterol treatment, indicating the absence of astroglial activation induced by hypercholesterolemia. Our results suggest that cerebellar ApoE does not contribute to the general cholesterol homeostasis outside of the brain and supports the view that this cerebellar ApoE is involved in paracrine and autocrine functions particularly related with synapse turnover and membrane remodelling of astroglial cells.
Brain Res Mol Brain Res 1994 Jan
PMID:Apolipoprotein E expression in the cerebellum of normal and hypercholesterolemic rabbits. 816 12

The aim of this study with rat hepatocytes was to describe the effect of okadaic acid (OKA) (a potent and specific inhibitor of protein phosphatases) on the biosynthesis, processing and/or secretion of various lipid and protein molecules. Gel radioautograms indicated that low concentrations of okadaic acid (100 nM) induced hyperphosphorylation of a number of hepatocyte phosphoserine/threonine residues in the Mr range of 35-220 kDa. The effects of okadaic acid on the morphology of the hepatocytes was time and dose-dependent; early changes included cell rounding, loss of typical Golgi staining of beta COP, and fragmentation of the Golgi compartment at the EM level. General hepatocyte cell functions such as protein synthesis, lactate dehydrogenase activity, and ATP levels were unchanged with 100 nM okadaic acid as were all hepatocyte functions carried out in the endoplasmic reticulum of these cells. As such, incubation with okadaic acid did not alter the biosynthesis of phosphatidylcholine (from labeled choline), or very low density lipoproteins (VLDL) from labeled fatty acids or glycerol. Likewise, the biosynthesis of various endoplasmic reticulum synthesized proteins (transferrin, albumin, apolipoprotein E, and HMG CoA Reductase) continued normally in the presence of okadaic acid. However, incubation with okadaic acid led to major changes in all hepatocyte functions normally carried out in the Golgi compartment; i.e., the incorporation of labeled ceramide into sphingomyelin was profoundly reduced, as was the Golgi-required packaging and secretion of various proteins synthesized in the endoplasmic reticulum. These findings point to the Golgi compartment as an specific target for okadaic acid and suggest that one or more okadaic acid-sensitive phosphoproteins may be involved in maintaining its normal structure and function.
Cell Mol Biol Res 1993
PMID:Effect of okadaic acid on hepatocyte structure and function. 829 41

The possibility was explored of synthesizing, from commercially available lipids, high density lipoprotein (HDL)-like particles (neo-HDL) with the same physico-chemical and biological properties as native HDL. A preparation method involving egg yolk phosphatidylcholine, cholesterol, and apoproteins from HDL led to the formation of particles with a composition, size, electrophoretic mobility, and density similar to those of discoidal HDL. In vitro experiments with isolated parenchymal liver cells showed that unlabeled HDL and neo-HDL competed for the same high affinity binding sites as did radiolabeled neo-HDL, whereas an excess of unlabeled low density lipoprotein was ineffective. In vivo experiments with radio-labeled neo-HDL indicated that neo-HDL showed a slow decay upon injection into rats, whereas the liver uptake did not exceed > 10% of the injected dose. The small additional liver uptake of radioactivity from neo-HDL, compared with HDL, was due to enhanced uptake by endothelial and Kupffer cells. Lactosylation of neo-HDL led to a markedly increased decay rate and a rapid uptake by rat liver (80% in 10 min). Parenchymal cells accounted for > 90% of the total liver uptake of radiolabeled lactosylated neo-HDL. Because the liver uptake of lactosylated 125I-neo-HDL could be blocked by preinjection of N-acetylgalactosamine, we conclude that the asialoglycoprotein receptor, which is specifically localized on parenchymal liver cells, is responsible for the avid liver uptake. With a fibroblast cell line transfected with the human asialoglycoprotein receptor, it was found that lactosylated neo-HDL binds with high affinity (Kd, 40 nM), in a galactose-specific way. It can be concluded that, with commercially available lipid components, HDL-like particles (neo-HDL) with virtually the same characteristics as found for native apolipoprotein E-free HDL can be reconstituted. Lactosylated neo-HDL, which is rapidly taken up by galactose-specific receptors on parenchymal liver cells, might be used to transport antiviral drugs specifically to parenchymal liver cells.
Mol Pharmacol 1993 Aug
PMID:Development of lipoprotein-like lipid particles for drug targeting: neo-high density lipoproteins. 835 72

Feeding a diet enriched with cholesterol/cholic acid (CCA) to rats caused defective plasma clearance of labeled chylomicron-like emulsions compared with clearance in chow-fed rats. When heparin was injected 5 min before an emulsion, the clearance of the emulsion in CCA-fed rats was significantly improved, and lipoproteins in the remnant and HDL fractions of plasma became enriched in apolipoprotein E. Injection of lactoferrin or poly-arginine inhibited the removal of emulsion or lymph chylomicron cholesteryl oleate in regular chow-fed rats. Poly-arginine but not lactoferrin inhibited the clearance of emulsion or chylomicron triolein also. The results demonstrate the involvement of charge interactions in both the lipolysis and remnant uptake steps of chylomicron clearance.
Biochem Mol Biol Int 1993 Apr
PMID:Charge effects on chylomicron clearance in rats. 850 43

The aim of the present investigation was to study the regulation of apolipoprotein E by two dietary nutrients, saturated fat and cholesterol, known to raise plasma cholesterol levels. ApoE is a protein component of several classes of lipoproteins including VLDL and HDL, and dietary lipids may regulate VLDL and apoE-containing HDL particles through their effects on apoE gene. Male rats and mice were fed the following 4 diets: control diet (C); high cholesterol diet with 0.5% cholesterol (HC); high fat diet with 20% hydrogenated coconut oil (HF); and high fat plus high cholesterol diet with 0.5% cholesterol and 20% fat (HF/ C). Plasma cholesterol levels remained unchanged on HC diet, but in mice VLDL-cholesterol increased by 31%. HF diet increased VLDL and LDL by 15-17% in rats, and 21% in mice. A combination of fat and cholesterol diet showed pronounced effects on plasma lipoprotein concentrations, raising apoB-containing particles by 21% and 44% in mice and rats, respectively. Plasma apoE levels increased significantly on all diets. The mechanism of regulation of increased plasma apoB and apoE levels was examined. Quantification of hepatic apoB mRNA showed a lack of correlation between plasma apoB and hepatic apoB mRNA levels, suggesting that posttranscriptional regulation increased plasma apoB-containing lipoproteins in animals fed saturated fat diets. Hepatic apoE mRNA levels increased significantly in animals fed cholesterol-rich diets. However, despite increased plasma apoE levels on diet containing only saturated fat, hepatic apoE mRNA did not change. Synthesis of apoE on the liver polysomes increased selectively on cholesterol-rich diets. These results suggest that cholesterol-rich diets altered apoE, in part, by transcriptional mechanism, and saturated fat-rich diets increased plasma apoE levels by posttranscriptional mechanism, possibly decreased receptor-mediated uptake of apoE-containing particles. The regulation of LDL receptor was also studied since plasma apoB and E levels may be altered by LDL receptor-mediated uptake by the hepatocytes. As expected, high cholesterol diet decreased LDL receptor mRNA by 30-40%. However, the LDL receptor protein on liver membranes did not change on any of the test diets in both animal species. Hepatic cholesterol content increased several fold selectively on high cholesterol diets. These findings suggest that: 1) both transcriptional and posttranscriptional mechanisms are important in regulating plasma apoB and E containing lipoproteins; 2) dietary cholesterol regulates apoE gene by a transcriptional mechanism and dietary saturated fat by posttranscriptional mechanism; and 3) changes in the hepatic apoE and LDL receptor mRNA are associated with the changes in intracellular cholesterol concentrations.
Mol Cell Biochem 1996 Feb 23
PMID:Regulation of the apolipoprotein E by dietary lipids occurs by transcriptional and post-transcriptional mechanisms. 870 Jan 60

B/A4 is the major component of brain amyloid plaque, one of the hallmarks of Alzheimer's disease (AD). B/A4 is a product of proteolytic processing of its precursor, the Alzheimer amyloid precursor protein (APP). Recently, apolipoprotein E (APO-E) has also been shown to be associated with Alzheimer's disease pathology because it is localized to plaques and tangles, and the gene encoding one of the isoforms of APO-E (E4) is associated with late-onset familial and sporadic AD. In addition, APO-E exhibits high affinity for binding to the B-peptide (B/A4). In this study, we have investigated changes in the steady state levels of APP, APO-E, and the astrocyte-specific marker, glial fibrillary acidic protein (GFAP) mRNA in the gerbil hippocampal CA1 region after a 10-min period of bilateral carotid occlusion-induced forebrain ischemia. Following this insult, we observed a loss of 90% of the CA1 neurons by 72 h post-ischemia. The mRNA levels on day 1 through day 7 post-ischemia were quantitated using an image analyzer. There was an increase in the transcription of APO-E and GFAP mRNAs, with the levels of APO-E mRNA being the highest (3-fold increase on day 7 post-ischemia) (P < 0.005). However, we did not see an increase in APP mRNA. In a parallel study [Hall, E.D. et al., Exp. Neurol., 135(1995) 17-27], we have also seen an increase in levels of APO-E and GFAP protein measured by immunocytochemistry. However, in contrast to the lack of an increase in APP mRNA, immunocytochemical measurement of APP did show an increase, perhaps due to delayed translation of previously formed mRNA. We suggest that neuronal injury or insult results in the induction of certain genes (and, therefore, protein synthesis) in the surrounding reactive astrocytes, and these proteins may contribute to post-injury amyloidogenesis.
Brain Res Mol Brain Res 1996 May
PMID:Induction of apolipoprotein E mRNA in the hippocampus of the gerbil after transient global ischemia. 873 65

Peptides eluted from murine Major Histocompatibility Complex (MHC) class II molecules are predominantly fragments of self proteins, which include apolipoprotein E, cystatin-c, transferrin receptor, MHC class II and Ii chains. These naturally processed self peptides are expected to be presented during ontogeny. Therefore, immune responses to these peptides in syngeneic hosts may be under physiological control so as to modulate auto-reactivity. As would be expected from our current understanding, T cells reactive to such antigens should be deleted or clonally anergized. To explore this possibility, we investigated the immunogenicity of a number of these self peptides in mice that express MHC class II, from which these peptides were eluted. T cell and antibody responses were measured following immunization of mice with the appropriate peptide. Surprisingly, many of these peptides were highly immunogenic in normal mice. T cells reactive to these self peptides are restricted by syngeneic MHC class II and were blocked by alpha CD4 antibodies. T cells primed with the native protein in vivo could be challenged with the appropriate self peptide in vitro. Some of the self epitopes induce Th1 cells as indicated by IFN-gamma but not IL-4 production and others induce Th2 cells. Antipeptide antibodies were detected only at higher doses of antigen. Our results suggest that T cells specific for many of the naturally processed self peptides are not deleted but tolerance to these peptides is still maintained in vivo. Presumably the high-affinity self-reactive T cells are deleted in the thymus and the low-affinity self peptide reactive T cells remain unresponsive to antigen challenge in vitro. Upon antigen priming in vivo, many of these self-reactive T cells become activated and readily respond to antigen challenge in vitro. These results point to the physiological control of the maintenance of tolerance to naturally processed self peptides.
Mol Immunol
PMID:Immune responses to self peptides naturally presented by murine class II major histocompatibility complex molecules. 876 Feb 74

The low density lipoprotein receptor-related protein (LRP) is a multifunctional cell surface receptor that binds to the protease inhibitor alpha 2-macroglobulin (alpha 2 M). LRP has also been identified as the apolipoprotein E (apoE) receptor that mediates lipid metabolism. Recently it has been reported that apoE4, one of three common isoforms of apoE, is a main risk factor of Alzheimer's disease (AD). Moreover, all three of these proteins are reported to accumulate in the senile plaques in the brains of Alzheimer's patients. To understand the roles of LRP in the normal development of the central nervous system (CNS) and in the pathogenesis of AD, we studied the developmental expression and localization of LRP mRNA in the CNS. We used Northern blot analysis to investigate the developmental profile of LRP mRNA in the rat brain. LRP mRNA was first detected as early as in 18-day-old embryonic rat brain and was continuously expressed thereafter. A particularly high level of expression of the mRNA was observed in the perinatal stage. We also determined the cellular distribution of LRP mRNA in the CNS of 20-day-old embryonic and 6-week-old adult rat brains by in situ hybridization using a digoxigenin-labeled antisense riboprobe to LRP mRNA. In the embryonic rat brain, LRP mRNA was highly expressed in most of the cells, mainly neurons and glial cells. In the adult rat, LRP mRNA was expressed mostly in neurons in both the brain and the spinal cord. These results suggest that LRP plays crucial roles in development of the brain.
Brain Res Mol Brain Res 1995 Oct
PMID:Expression and distribution of low density lipoprotein receptor-related protein mRNA in the rat central nervous system. 877 44

This study examines the relationship between the levels of apolipoprotein E (apoE) and apolipoprotein J (apoJ, also designated as clusterin) as a function of apoE genotype in the hippocampus and cortex of Alzheimer disease (AD) subjects. These two lipophilic proteins which are involved in the maintenance of lipid homeostasis are both synthesized in the brain by astrocytes. Results indicate a reduction of apoE levels in the hippocampus and frontal cortex that is proportional to the apoE4 allele dose. Conversely, apoJ (clusterin) levels were found to increase proportionately to the number of apoE4 allele dose. These results suggest a compensatory induction of apoJ (clusterin) in the brain of apoE4 AD subjects showing low brain levels of apoE.
Brain Res Mol Brain Res 1995 Oct
PMID:Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer disease. 877 59

The presenilin-1 (PS-1) gene on chromosome 14 carries mutations which cosegregate with early-onset familial Alzheimer's disease. We quantified PS-1 mRNA in post-mortem mid-temporal and superior frontal cortices from 14 Alzheimer's disease subjects, 9 non-demented controls and 5 subjects with other neurological diseases using solution hybridisation-RNase protection assay. APP and APLP2 mRNAs had previously been quantified in these samples (Johnston et al. (1996) Mol. Brain Res., in press) and subjects were apolipoprotein E (APOE) genotyped. There were no significant differences between PS-1 mRNA levels per pg total RNA in mid-temporal or superior frontal cortices of the Alzheimer's disease subjects, compared to controls. PS-1 mRNA levels corresponded to 10% of total APP and 30% of APLP2 mRNA levels, and were not significantly affected by age, post-mortem delay, tissue pH, or APOE genotype. PS-1 mRNA showed significant positive correlations with APP and APLP2 mRNA levels in mid-temporal cortex and with APP mRNA in superior frontal cortex. This may reflect a co-regulation of the expression of these genes, or the fact that they are expressed in similar neuronal populations.
 ...
PMID:Quantification of presenilin-1 mRNA in Alzheimer's disease brains. 883 Jun 58


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