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Biomedical subjects

E Windler

Publications and source records attributed to E Windler.

At least 37 records · Page 2Linked to original sources
PubMed1996

Differences in the mechanisms of uptake and endocytosis of small and large chylomicron remnants by rat liver.

Initial binding and subsequent endocytosis of small and large chylomicron remnants by rat liver were compared. Small and large chylomicrons were obtained from mesenteric lymph of glucose- or fat-fed rats, respectively. The low-density lipoprotein (LDL) receptor was up- and down-regulated as shown by LDL receptor messenger RNA (mRNA). The rate of removal of small chylomicron remnants by isolated perfused rat livers followed closely the activity of the LDL receptor. When mRNA was undetectable, the uptake was as low as that of lymphatic small chylomicrons. In contrast, the uptake of large chylomicron remnants into perfused rat livers was unaffected by changes of the LDL-receptor activity, but significantly reduced after livers were flushed with heparin or heparinase. Large chylomicron remnants were cleared from plasma much faster than small chylomicron remnants, but were more slowly internalized into hepatocytes. Both, small and large chylomicron remnants entered the pathway of receptor-mediated endocytosis as shown by electron microscopy and analysis of isolated endosomes. Yet, large chylomicron remnants were taken up into the compartment of uncoupling of receptors and ligands and multivesicular bodies at a much slower rate. This was independent of the activity of the LDL receptor and the heparin-releasable binding site. From these findings it is concluded that large chylomicron remnants initially bind rapidly to surface components other than the LDL receptor, one of which may be hepatic lipase. Yet, the consecutive internalization is slow. In contrast, small chylomicron remnants are removed at a slower rate from plasma, binding predominantly to the LDL receptor, but are more readily taken up into endosomes.

Animals↗
PubMed1996

[Current developments in prevention of coronary heart disease].

The Scandinavian Simvastatin Survival Study (4S-Studie) has provided proof beyond any doubt that reduction of plasma cholesterol decreases mortality. The enormous rise of morbidity and mortality from cardiovascular disease in both gender calls for preventative measures as an urgent task. With a reduction of cardiac events by 30-40% and of mortality in the same order of magnitude, cholesterol lowering and increase in HDL-cholesterol are most effective measures for the treatment of coronary artery disease. However, not treatment of late stages of the disease, but primary prevention to reduce the incidence of coronary artery disease in this country should be the principle aim. Thus, the international guidelines for the treatment of lipid disorders considering the individual patient's risk profile have been revised.

Anticholesteremic Agents↗
PubMed1996

[Prevention of cardiovascular diseases by hormone replacement in postmenopause].

Cardiovascular disease is the most important cause of death even among women. After menopause there is a steep increase in risk factors like LDL-cholesterol and lipoprotein (a) as well as the incidence of hypertension and diabetes mellitus. This is followed by a rise especially in coronary artery disease. Therefore women too have to be included in prevention programs for cardiovascular disease by normalizing risk factors. One means is hormone replacement therapy. Estrogens lower LDL-cholesterol by up to 20% and increase HDL-cholesterol up to 30%. This effect remains even after addition of a suitable progestin. Numerous large scale studies indicate that every other cardiovascular death can be prohibited by the simple measure of hormone replacement therapy. Because of the high rate of cardiovascular disease low incidences of adverse events cannot prevent the marked decrease in total mortality.

Adult↗
PubMed1996

Endocytic mechanisms for uptake and metabolism of chylomicron remnants in the liver.

Removal of small chylomicron remnants by perfused rat livers closely correlates with the LDL-receptor mRNA modulated by various interventions. In contrast, removal of remnants of large chylomicrons is not appreciably influenced by the activity of the hepatic LDL-receptor. Their primary removal depends on a heparinase-sensitive binding site. Transient and stable transfection of the cDNAs of the two subunits of the human asialoglycoprotein receptor markedly increased the binding capacity for chylomicron remnants suggesting the asialoglycoprotein receptor to be an alternative mechanism for remnant removal. Some species can edit apolipoprotein B-100 mRNA and thus secret apolipoprotein B-48 containing lipoproteins of hepatic origin. Generally these animals have lower cholesterol levels and a more favorable lipoprotein profile.

Animals↗
PubMed1995

Trials of the effects of drugs and hormones on lipids and lipoproteins.

Recent trials on the efficacy of drugs and hormones in lowering cholesterol and correcting lipoprotein profiles are reviewed. Emphasis is placed on the risk-benefit ratio, which determines the clinical value of therapeutic regimens. Whereas 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors have set a standard for treatment of hyperlipidaemia, the role of hormone replacement therapy in postmenopausal women in the prevention of coronary artery disease has more recently become better defined.

Clinical Trials as Topic↗
PubMed1994

[Localized fibrous pleural mesothelioma. Value of image-producing methods for the differentiation from supradiaphragmatic tumors of the liver].

A 38-year-old woman in good health suddenly developed pain in the right chest and mild dyspnoea. She reported two bronchial infections in the preceding year. Physical examination revealed cyanosis of the lips and finger clubbing, slightly dulled percussion sounds and decreased breath sounds at the basis of the right chest, but no other abnormalities. Activity of the tumour marker CA 125 was raised (60 kU/l). The chest radiography showed a shadow in the right lower segment, resembling a high diaphragm. Computed tomography failed to separate the abnormal structure from the liver substance. Needle puncture discovered a small haemorrhagic effusion with mesothelial cells. Magnetic resonance imaging and a scintigraphy of the liver provided evidence that the mass was separate from the liver. At thoracotomy a tumour, 20 x 15 x 10 cm in size and connected by a pedicle to the pleura, was identified and excised. Immunocytochemical tests showed it to be a fibrous pleural mesothelioma without signs of malignancy. The patient was discharged 10 days postoperatively in good general condition.

Adult↗
PubMed1994

Annexin VI, a marker protein of hepatocytic endosomes.

Three highly purified endosomal fractions from rat liver were used to purify and characterize a major protein of endosomal membranes. Intravenously injected ligands, which are taken up via receptor-mediated endocytosis, accumulate first in the fraction of intermediate density, the compartment of uncoupling of receptors and ligands. The high density membranous fraction is highly enriched in a receptor recycling compartment. The endosomal fraction of lowest density is composed of multivesicular bodies, which appear to be the immediate prelysosomal compartment. The most prominent membrane protein of these endosomes is one of 68 kDa, as revealed by silver and Coomassie Brilliant Blue staining of SDS-gel electrophoretograms. This protein dominates profiles obtained from purified membranes of the compartment of uncoupling of receptors and ligands, multivesicular bodies, and receptor recycling compartment, but is greatly reduced in those obtained from plasma membranes and lysosomes. The 68-kDa protein was purified from endosomes and digested with trypsin, and cleavage products were analyzed by protein sequencing. The tryptic fragments of the endosomal 68-kDa protein share 96% identity with corresponding sequences of mouse annexin VI and 91% identity with sequences of human annexin VI. Using immunoblots, high concentrations of annexin VI with an apparent molecular mass of 68 kDa were detected in endosomal membranes by specific antiserum to annexin VI. Significant amounts of annexin VI were also detected in Golgi membranes. Yet, the concentration was substantially lower than that of the three endosomal fractions. The association of annexin VI with endosomal membranes is calcium-dependent, as revealed by the complete solubilization from endosomal membranes by EGTA. Incubation of intact endosomes with Pronase leads to a complete degradation of annexin VI without any detectable disintegration of proteins localized on the luminal surface of endosomal membranes. Evidently, annexin VI is localized on the cytoplasmatic leaflet of the membrane of endosomes and may be of significance for their intracellular trafficking.

Amino Acid Sequence↗
PubMed1994

The prognostic value of hypocholesterolemia in hospitalized patients.

Clinical observations show that severe illness often leads to hypocholesterolemia. To verify this finding and to define the relationship between serum cholesterol and a patient's prognosis, a study was conducted in two large hospital populations. Of 24,000 and 61,463 adult patients (populations I and II) an average of 3.8% and 3.6% died in hospital, respectively. The mean serum cholesterol levels of patients who died was significantly lower than that of those who survived (163.6 mg/dl versus 217.8 mg/dl; P < 0.0001). The average cholesterol of surviving patients was similar to that of 6,543 healthy controls. During hospitalization serum cholesterol levels of < or = 100 mg/dl were encountered in 1.2% and 3.6% of patients of populations I and II, respectively. The mortality of these hypocholesterolemic patients was about tenfold higher than average and showed a strong, inverse, linear relationship with serum cholesterol concentrations. Patients whose serum cholesterol level dropped to less than 45 mg/dl did not survive. These data show that in severely ill patients serum cholesterol may decline to very low concentrations, and the prognosis is reflected by the degree of hypocholesterolemia, which thus may serve as a clinically useful prognostic parameter.

Adult↗
PubMed1994

Selective uptake of high-density lipoprotein-associated cholesteryl esters and high-density lipoprotein particle uptake by human monocyte-macrophages.

High-density lipoprotein (HDL) cholesteryl esters (CE) are taken up by many cells without parallel uptake of HDL apolipoproteins. This selective uptake of HDL CE was investigated in human monocyte-derived macrophages (HMM). HDL3 (d = 1.125-1.21 g/ml) was labeled in its apolipoprotein A-I moiety with 125I and in its CE moiety with [3H]cholesteryl oleyl ether. Cultured human monocyte-macrophages were incubated in the presence of doubly labeled HDL3 followed by determination of tracer uptake. HMM took up HDL3 particles as indicated by the uptake of HDL3 apolipoproteins. Uptake of HDL3-associated CE tracer was in significant excess of that due to HDL3 particle uptake indicating selective uptake of CE. Increased cell cholesterol due to preincubation with acetylated low-density lipoprotein (LDL) down-regulated selective uptake by HMM. According to several experimental approaches, selective uptake of HDL3 CE was independent from cell-secreted products, LDL receptor-mediated endocytosis or HDL3 retroendocytosis. The intracellular catabolism of HDL3 CE was investigated with HDL3 labeled in its CE moiety with [3H]cholesteryl oleate. The lysosomal inhibitor chloroquine had no effect on CE hydrolysis indicating that CE selectively taken up is hydrolyzed independently from lysosomes. In conclusion, HMM selectively take up HDL3-associated CE. The cellular mechanism of selective uptake is independent from endocytosis or retroendocytosis. Intracellularly, HDL3 CE selectively taken up are catabolized independently from lysosomes.

Apolipoprotein A-I↗
PubMed1994

Requirements for editing in the genomic RNA of hepatitis delta virus.

Hepatitis delta virus is a satellite of the hepatitis B virus which provides the surface antigen for the viral coat. The genome of the hepatitis delta virus consists of a single-stranded, circular RNA of 1679 nucleotides which forms a rod structure due to a high extent of self homology and which replicates via synthesis of an antigenomic RNA in a rolling circle mechanism similar to plant viroids. The antigenomic RNA contains the open reading frame for the delta-antigen which exists in two isoforms, p24 and p27. The formation of these two isoforms is explained by RNA editing at nucleotide 1012 which changes the stop translation codon UAG at amino acid residue 196 into the codon UGG for tryptophan and extends the open reading frame for the synthesis of p27. In order to investigate whether the editing occurs cotranscriptionally during RNA replication or is a posttranscriptional base modification in the genomic or antigenomic RNA, replication defective deletion mutants of the HDV genome were constructed and expressed in COS-7 cells. Editing was demonstrated in non-replicating fragments of genomic HDV RNA but not in antigenomic HDV RNA fragments. The sequences from nucleotide position 337-1200 of the genomic RNA were sufficient to enable low levels of editing. Editing at position 1012 required the opposite strand of the RNA rod from nucleotide position 337-783. Replicating circular HDV RNA was much more efficiently edited than non-replicating full length genomic HDV RNA. Expression of delta-antigen in trans did not complement the low editing efficiency of replication defective genomic HDV RNA. These results demonstrate posttranscriptional U to C editing in the genomic HDV RNA and exclude misincorporation during HDV RNA replication as the editing mechanism. The minimal structural requirements for HDV RNA editing reside between nucleotide position 337-1200.

Animals↗
PubMed1993

Selective association of lipoprotein cholesteryl esters with liver plasma membranes.

High-density lipoprotein (HDL) cholesteryl esters are taken up by hepatocytes without parallel uptake of HDL apolipoproteins. This selective uptake of HDL cholesteryl esters is mediated by a non-endocytotic mechanism. Recently, selective uptake of cholesteryl esters also from low-density lipoprotein (LDL) was demonstrated. In this study, the role of the plasma membrane in selective uptake by the liver was investigated. Plasma membranes were prepared from rat liver or from human Hep G2 hepatoma cells. Human HDL3 (d = 1.125-1.21 g/ml) was either radioiodinated or labeled with [3H]cholesteryl oleate. Human low-density lipoprotein (d = 1.019-1.05 g/ml) was labeled in its protein and in its lipid moiety as well. Labeled lipoproteins, unlabeled lipoproteins and membranes were incubated. After separation by ultracentrifugation, apparent lipoprotein particle association with membranes was determined. Plasma membranes from rat liver and Hep G2 cells bound 125I-HDL3, indicating specific HDL3 particle binding. With both types of membrane, apparent HDL3 particle association according to [3H]cholesteryl oleate-labeled HDL3 was in significant excess on that due to 125I-HDL3. This indicates selective, i.e., particle binding independent, association of cholesteryl esters with the membrane. Excess unlabeled HDL3 competed for selective association, indicating a specific process. Selective association of HDL3 cholesteryl esters was concentration-, time-, temperature-dependent; however, parameters differed from HDL3 particle binding. HDL3 was modified by nitration; this modification inhibited HDL3 particle binding in contrast to unchanged selective association. These results suggested distinct membrane sites for HDL3 particle binding and selective cholesteryl ester association. Regulation of selective association was investigated. Hep G2 cells were cholesterol-loaded or cholesterol-depleted. Cellular cholesterol-loading down-regulated selective association of HDL3 cholesteryl esters with isolated membranes prepared from these cells. In parallel, selective uptake of HDL3 cholesteryl esters by Hep G2 cells was down-regulated in cholesterol-loaded cells. This parallel regulation of selective association with membranes and selective uptake by cells suggests a functional relationship. LDL, radiolabeled in its protein and in its lipid moiety, was incubated with liver plasma membranes. Besides LDL holo-particle receptor binding, also LDL cholesteryl esters were selectively associated with membranes. These data showed that selective association with membranes is not restricted to HDL but can occur from LDL as well. It is concluded that HDL3 as well as LDL cholesteryl esters can selectively be associated with hepatic plasma membranes, i.e., independent from particle binding. Results suggest an important role of the plasma membrane in the mechanism of selective cholesteryl ester uptake by the liver.

5'-Nucleotidase↗
PubMed1993

Dissection of compartments in rat hepatocytes involved in the intracellular trafficking of high-density lipoprotein particles or their selectively internalized cholesteryl esters.

The trafficking of apolipoprotein E-deficient high-density lipoprotein particles and of their component cholesteryl esters in rat hepatocytes was studied. Human high-density lipoprotein 3, labeled with two nondegradable, intracellularly trapped tracers in their apolipoprotein A-I and their cholesteryl esters, were injected into rats, and five subcellular hepatocytic fractions were isolated at various time intervals. In control experiments with homologous lipoproteins, doubly labeled rat high-density lipoproteins depleted of apolipoprotein E were used. In endosomes and lysosomes the two labels were recovered at near unity, indicating that high-density lipoproteins are endocytosed as particles, transported to early and late endosomes and finally subjected to lysosomal degradation. No significant amounts of label were found in receptor-recycling endosomes. In contrast to label of those of low-density lipoproteins, label of component protein and cholesteryl esters of high-density lipoproteins from isolated endosomes floated at different densities in gradient ultracentrifugation, indicating early disintegration of high-density lipoprotein particles. In contrast to the endocytic organelles, in the whole liver, label of high-density lipoprotein-associated cholesteryl esters exceeded the label of high-density lipoprotein-associated apolipoprotein A-I twofold to threefold. This finding is compatible with selective uptake of high-density lipoprotein cholesteryl esters in addition to uptake of high-density lipoprotein particles. The excess cholesteryl esters accumulated in a nonendosomal fraction, whose major proteins differed from the integral proteins of endosomes. These data suggest two distinct intracellular routes of hepatocytic high-density lipoprotein trafficking in vivo. High-density lipoproteins free of apolipoprotein E are internalized intact by hepatocytes, are predominantly transported to early and late endosomes and are finally subjected to lysosomal degradation. High-density lipoprotein particles do not undergo retroendocytosis in hepatocytes. In addition, high-density lipoprotein-associated cholesteryl esters can be taken up by hepatocytes selectively. They, however, accumulate in a nonendosomal, nonlysosomal compartment.

Animals↗