Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.16.3.1 (ceruloplasmin)
 5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate our earlier hypothesis that carbohydrates play a regulatory role in the intracellular transport of secretory glycoproteins, we used 1-deoxynojirimycin (DNJ), and inhibitor of glucosidase I and II of the rough endoplasmic reticulum (RER), to modify the structure of N-linked glycan moieties of secretory glycoproteins of human hepatoma (Hep G2) cells in culture. Using a pulse-chase protocol, we found that treatment of Hep G2 cultures with 1.25 mM DNJ markedly reduced the rate of secretion of alpha 1-protease inhibitor, ceruloplasmin, and alpha 2-macroglobulin, but had no effect on the export of fibronectin, alpha-fetoprotein and transferrin, nor on albumin which lacks carbohydrate. For example, 50% of newly synthesized alpha 1-protease inhibitor, the glycoprotein most dramatically affected, was secreted by 27 min in control cultures versus 110 min in DNJ-treated cultures. Percoll gradient cell fractionation analyses revealed that DNJ inhibited transport of the affected secretory glycoproteins in the RER segment of the ER/Golgi pathway. For example, 50% of newly synthesized alpha 1-protease inhibitor was lost from the RER fraction by 10 min in untreated cells, but 70 min was required for the transport of a similar amount of protein in DNJ-treated cells. DNJ treatment also inhibited the rate at which the N-linked glycan moieties of the affected glycoproteins became resistant to endo H in the Golgi. Since the glycan moiety of secreted forms of the affected glycoproteins were fully processed to the complex structure, suggesting escape from DNJ inhibition, we concluded that removal of terminal glucose residues from the glycan chain of secretory glycoproteins is required for their transport from the RER to the Golgi. We suggest that the oligosaccharide moieties on alpha 1-protease inhibitor, ceruloplasmin and alpha 2-macroglobulin form part of the binding site for a receptor which regulates transport of these glycoproteins.
 ...
PMID:Differential effects of 1-deoxynojirimycin on the intracellular transport of secretory glycoproteins of human hepatoma cells in culture. 243 31

Previous studies in this laboratory (1) have shown that tunicamycin-treatment inhibits the secretion of three secretory glycoproteins--alpha 2-macroglobulin, ceruloplasmin, and alpha 1-protease inhibitor in human hepatoma (Hep G2) cell cultures. In the present study, we have investigated (i) their site of accumulation within the endoplasmic reticulum/Golgi pathway, and (ii) the solubility characteristics of these unglycosylated proteins. Using percoll density gradient centrifugation, we found that tunicamycin-treatment markedly inhibited the transport of alpha 2-macroglobulin, ceruloplasmin and alpha 1-protease inhibitor from the rough endoplasmic reticulum. However, there was no detectable changes in their solubility properties as both the glycosylated and unglycosylated species were associated with the 100,000 xg supernatant fraction following disruption of the microsomal fraction (i) with 0.2% Triton X-100 and (ii) by repeated freeze-thaw cycles. Also no evidence of protein aggregation was detected by liquid chromatography of the unglycosylated proteins on Bio-Gel A-1.5 column.
 ...
PMID:Accumulation of unglycosylated liver secretory glycoproteins in the rough endoplasmic reticulum. 247 24

We have previously shown that newly synthesized liver secretory proteins are exported at three distinct characteristic rates, with intracellular retention half-times of 110-120 min (e.g. transferrin), 75-80 min (e.g. ceruloplasmin), and 30-40 min (e.g. alpha 1-protease inhibitor) (J. B. Parent, H. Bauer, and K. Olden (1985) Biochim. Biophys. Acta, in press). In the present study we have determined the average time required for specific glycoproteins to move through the various compartments of the intracellular transport pathway, consisting of endoplasmic reticulum and Golgi complex. Localization in particular compartments was monitored by the use of the following complementary approaches: (i) Percoll density gradient fractionation of the subcellular organelles, (ii) sensitivity of the glycan moiety of N-linked glycosylation to endo-beta-N-acetylglucosaminidase H, and (iii) by the lectin-binding characteristics. The cell fractionation studies revealed that alpha 1-protease inhibitor, ceruloplasmin, and transferrin were transported from the rough endoplasmic reticulum with a retention half-time of 10, 30, or 45 min, respectively. Measurements of the rate at which newly synthesized glycoprotein became endo H-resistant (an event localized near the medial region of Golgi) demonstrated that it took 60-70, 30, and 18 min for 50% of transferrin, ceruloplasmin, and alpha 1-protease inhibitor, respectively, to reach the medial Golgi. Consistent with this finding, maximal binding of transferrin to wheat germ agglutinin (also a medial Golgi event) and Ricinus communis agglutinin I (a trans Golgi event) required 75 and 90 min, respectively, and maximal binding of ceruloplasmin to both lectins occurred in approximately 30 min. Maximal binding of alpha 1-protease inhibitor to wheat germ agglutinin and Ricinus communis agglutinin I required 15 and 30 min, respectively. The results presented here clearly indicate that (i) the time required for protein secretion cannot be entirely accounted for by lag in transport from the rough endoplasmic reticulum to the Golgi since the glycoproteins examined are retained in the former organelle for no more than two-fifths of the total intracellular retention half-time, and (ii) the variability in rates of protein secretion is not due solely to differences in rates of transport from the rough endoplasmic reticulum to the Golgi as variability in retention within the Golgi is also demonstrated. The results are discussed in terms of their compatibility with receptor-mediated transport of glycoproteins in both the endoplasmic reticulum and Golgi.
 ...
PMID:Variability in transport rates of secretory glycoproteins through the endoplasmic reticulum and Golgi in human hepatoma cells. 298 65

This is a broad review (140 literature citations) of the possible effects of oral contraceptives on the liver. The oral contraceptives considered consist of combined preparations of estrogens and progestogens although the so-called "minipills" contain only a progestogen. The effects are divided into 1) decrease in excretory liver function; 2) influence on bile acid formation, including cholesterol metabolism; 3) increased synthesis of various transport proteins (ceruloplasmin, transferrin, thyroxine-binding protein, and cortisol-binding protein); 4) the effects of increased tissue circulation caused by sexual hormones and anabolic steroids as a cause for more frequent cavernous angiomas and peliosis hepatis; 5) interference with the metabolism of other drugs by the competitive action of the hepatic metabolites of steroid hormones. This includes the increased formation of delta amino levulinic-acid synthetase, the key enzyme for porphyrin synthesis. The gestagen component of oral contraceptives is responsible for enzyme induction in the smooth endoplasmic reticulum. Morphological liver changes caused by oral contraceptives include parenchyma changes, hepatosis, reactive hepatitis, hepatitis resembling viral hepatitis, vascular changes, sinusoid ectasia, Budd-Chiari syndrome, hyperplasias and neoplasias, focal nodular hyperplasia, adenoma and liver cell carcinoma.
 ...
PMID:[Effects of oral contraceptives on liver function and structure]. 332 30

Patients with chronic heart failure (CHF) can often develop such diseases as hepatitis of viral etiology, alcoholic hepatitis, drug affection of the liver and other diseases masked as congestive liver. In most cases CHF concomitant liver diseases have an atypical course with a tendency to a chronic course. CHF is one of the important pathogenetic mechanisms lying in the basis of chronicity of concomitant liver diseases. Refractory CHF, inconsistency of the hemodynamic indices of persistent hepatomegaly must lead a physician to the detection of probable independent liver diseases complicating the syndrome of heart failure. CHF is a factor causing an enhanced fibrosing liver reaction. An important diagnostic test of fibrinogenesis lying in the basis of chronicity of liver diseases, is the determination of enzymatic markers reflecting synthesis and catabolism of the main substance of connective tissue. Change in the levels of haptoglobin, ceruloplasmin and glutamic acid dehydrogenase is an indirect sign of damage of the liver parenchymal endoplasmic reticulum. These indices can serve as differential criteria of the prevalence of cardiovascular disorders in the liver or concomitant independent liver diseases.
 ...
PMID:[Pathogenetic mechanisms of chronicity in liver diseases in patients with circulatory failure]. 361 41

Copper deficiency can reduce the productivity of livestock. The effect of copper deficiency on a number of copper enzymes and copper-dependent systems is discussed, to highlight the areas where their role needs to be clarified. Special reference is made to cytochrome c oxidase, lysyl oxidase, superoxide dismutase and endoplasmic reticulum enzymes and to their role in the expression of disease. The modification of microbiological insult by a change in superoxide dismutase activity without any other direct metabolic consequences is discussed, to introduce the concept of an external challenge being necessary before any effect of an otherwise sub-clinical copper deficiency is observed. The changes in activity of the various copper enzymes are described in clinical and experimentally induced copper deficiency in sheep and cattle, two species in which copper deficiency can have economic consequences. The diagnostic value of various blood markers, such as copper, caeruloplasmin and erythrocyte superoxide dismutase is discussed. The measured degree of hypocupraemia is related to different types of sampling (e.g. plasma or serum), physiological status (e.g. in the pre- and postpartum cow), changes that occur in the neonate, and also to the effect of the acute-phase reaction. The use of erythrocyte superoxide dismutase as a marker for the copper status of sheep and cattle is compared with more conventional markers such as plasma concentration of copper. The use of blood markers to map the extent and location of hypocupraemia (due to reduced copper intake or availability) among suckler (beef) herds in Northern Ireland is also discussed.
 ...
PMID:Copper deficiency in ruminants. 611 May 25

The subcellular localization in rat liver cells of retinol-binding protein (RBP), prealbumin, ceruloplasmin, albumin, and class I transplantation antigen chains was investigated by radioimmunoassay determinations. The concentration of RBP was high in the rough and smooth endoplasmic reticulum (SER). The relative concentrations of prealbumin, ceruloplasmin and albumin were similar in the endoplasmic reticulum fractions and in the Golgi fraction. Neither of the proteins were found in significant amounts in the post-microsomal supernatant nor in the plasma membrane. The concentrations of the class I transplantation antigen chains were higher in the Golgi fraction than in the endoplasmic reticulum fractions. In the rough endoplasmic reticulum (RER) fraction ceruloplasmin and the class I antigens partially interact with high-molecular weight (MW) components, presumably membrane-bound glycosyltransferases. RBP, prealbumin and albumin seemed to be present in free form within the microsomal lumen. In vitamin A deficiency the RBP and to a lesser extent the prealbumin concentrations in the endoplasmic reticulum fractions were significantly increased, as compared to fractions from normal livers. This suggests that the presence of vitamin A is a prerequisite for the transport of RBP from the endoplasmic reticulum to the Golgi complex. The intracellular concentrations of albumin and ceruloplasmin were not significantly altered by vitamin A deficiency. In contrast, the amounts of the class I antigen heavy chains were found to be increased.
 ...
PMID:Subcellular localization in normal and vitamin A-deficient rat liver of vitamin A serum transport proteins, albumin, ceruloplasmin and class I major histocompatibility antigens. 633 57

Superoxide dismutase (SOD) activity, plasma caeruloplasmin activity and the level of whole tissue and subcellular lipoperoxides have been determined in normal and neoplastic tissues from control and tumour-bearing mice, measurements being made nine, twelve and fifteen days after the inoculation of Lewis lung carcinoma cells. SOD activity of host liver and lung tissues did not vary significantly from those of the control animals. Blood SOD activity of the tumoured animals was markedly elevated on the ninth and twelfth days after inoculation, decreasing to control levels on the fifteenth day. Tumor SOD diminished from activity on the ninth day which was greater than that for control lung to a level significantly lower than that for control lung on the twelfth and fifteenth days after inoculation. The presence of a tumor did not appear to affect plasma caeruloplasmin oxidase levels. The lipoperoxide level of hepatic tissue rose significantly as the tumour progressed. In the lung tissue the lipoperoxides decreased from a level four times higher on the ninth day to one not significantly different from that of the controls. Tumour lipoperoxides were about twice the level of hepatic tissue and of the order of ten-fold greater than those of lung. The level of lipoperoxide in the plasma of tumoured mice did not differ markedly from that of control mice. Assays of lipoperoxide in subcellular fractions of liver, lung and tumour tissue revealed that the elevated lipoperoxide was principally synthesized in the endoplasmic reticulum.
 ...
PMID:Superoxide dismutase activity, caeruloplasmin activity and lipoperoxide levels in tumour and host tissues of mice bearing the Lewis lung carcinoma. 688 27

To analyze the importance of the endoplasmic reticulum oxidizing state for the folding and aggregation of newly made polypeptides, we have incubated intact HepG2 hepatoma cells in the presence of dithiothreitol. When dithiothreitol-treated cells were extracted under nondenaturing conditions immunoprecipitates of newly synthesized albumin showed a complex polypeptide profile. Using direct and sequential immunoprecipitation protocols we identified eight other polypeptide chains, transferrin, plasminogen, ceruloplasmin, alpha 2-macroglobulin, the three fibrinogen chains, and haptoglobin, that were among the proteins co-immunoprecipitated with albumin. The heterotypic aggregates are larger than several hundred kilodaltons and are stabilized by noncovalent interactions. Of the 10 polypeptide chains we examined, only one, alpha 1-antitrypsin, failed to aggregate. This protein is distinguished from the others by the absence of disulfide bonds. We propose a model in which the function of the oxidizing conditions of the endoplasmic reticulum is to promote the rapid formation of disulfide bonds that stabilize adhesive domains in a buried state, thus preventing "global" heterotypic aggregation of newly synthesized chains.
 ...
PMID:Dithiothreitol treatment induces heterotypic aggregation of newly synthesized secretory proteins in HepG2 cells. 807 73

Biosynthesis and secretion of ceruloplasmin (CP) in rat liver has been studied in order to elucidate its role in the distribution, transport and excretion of copper in the body. The kinetics and topography of CP synthesis, intracellular transport and secretion were followed using in vivo pulse-chase experiments. It was found that the newly formed CP was firmly bound to endoplasmic reticulum membranes in the hepatocytes. Liver slices incubated in vitro with [35S]methionine were characterized by a two-stage release of [35S]CP into the medium. After 30-min incubation the medium contained 200 kDa CP-like protein, while after 120 min the secretion of 130 kDa CP was demonstrated. The pulse-labelling experiments with [35S]methionine in rats with catheters inserted into the carotid artery and the common bile duct revealed the polar secretion of two distinct CP species differing in molecular structure and secretion rate. The slowly secreted CP isoform is the authentic serum CP, while the rapidly secreted CP is the specific biliary CP. The physiological function of biliary CP and its role in the pathogenesis of Wilson's disease are discussed.
 ...
PMID:[Biosynthesis of two molecular forms of ceruloplasmin in rat liver and their polar secretion into the blood stream and bile]. 829 51


1 2 3 Next >>