Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitonchondria isolated from the Morris hepatoma 7777 demonstrated a markedly different phospholipid composition from those of control mitochondria, both with respect to the amounts of the various types present and the fatty acid composition. The level of polyunsaturated fatty acids in the mitochondrial phospholipids was lowered, wheras there was an increase in the level of monounsaturated fatty acids. Moreover, the usual distribution of saturated fatty acids at position 1 and polyunsaturated fatty acids at position 2 does not exist in hepatoma phospholipids; a high percentage of monounsaturated fatty acids was found at both positions. The cardiolipin content was lower in hepatoma mitochondria (3.7%) than in livers of animals with hepatomas (5.2%). There was, however, some compensation in the amount of acidic phospholipids in these mitochondria due to an increase in phosphatidylserine (4.9% versus 1.3%). The force-area curves of the hepatoma phospholipids spread on a monomolecular film demonstrated a smaller area per molecule than those from liver mitochondria. The zeta potential of liposomes of the hepatoma phospholipids (-45) was less than those of control mitochondria (-81), as determined by microelectrophoresis. The calcium-stimulated phospholipase A activity of the hepatoma mitochondria appeared to be more readily expressed than the same activity in liver organelles. The maximal activity was lower, however, than that noted in liver mitochondria. Furthermore, by following the incorporation of [3H]ethanolamine into mitochondria phospholipids, it was established that the conversion of glycerophosphorylethanolamine to glycerophosphorylcholine was increased in the hepatoma. These observations suggest dramatic changes in phospholipid metabolism in the hepatoma, at the level of both the endoplasmic reticulum and the mitochondrion. Accompanying the changes in phospholipid compositon and metabolism were alterations in mitochondrial energy-linked processes. The hepatoma mitochondria demonstrated lower respiratory control ratios even when isolated in an isotonic solution containing 1mM ethylenediaminetetraacetate and bovine serum albumin (0.5 mg/ml). This was due to increased state 4 respiration.
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PMID:Alteration of mitochondrial function and lipid composition in Morris 7777 hepatoma. 18 46

Serum levels of phospholipase A2 (PLA2) activity have been shown to be elevated in cases of septic shock and rheumatoid arthritis. The cellular origin of serum PLA2, however, is not known. In this report, we demonstrate that human group II PLA2 expression and secretion are induced in hepatoma cells (HepG2) following treatment with interleukin-6 (IL-6), tumor necrosis factor (TNF), and interleukin-1 (IL-1). Of the three cytokines, IL-6 is the most potent. Significant synergy is observed between IL-6 and IL-1 and between IL-6 and TNF, but not between IL-1 and TNF. PLA2 induction does not occur in human YT cells, which are known to have receptors for both IL-1 and IL-6, indicating that the regulatory mechanism involved is cell type-specific. The results of RNA blot analysis indicate that the PLA2 gene is regulated in HepG2 cells at the pretranslational level. Induction of PLA2 synthesis in HepG2 cells in response to these cytokines resembles the induction of the acute phase plasma proteins which are synthesized in cultured hepatocytes and hepatoma cells following exposure to the same cytokines and in liver in response to inflammation and infection. In addition, a putative IL-6-responsive element, which is homologous to a similar element found in several acute phase genes, is present in the 5'-promoter-proximal region of the PLA2 gene. These results suggest that serum PLA2 is synthesized in and secreted from liver cells in response to inflammatory stimuli, mediated primarily by IL-6, and therefore should be classified as an acute phase protein.
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PMID:Induction of phospholipase A2 gene expression in human hepatoma cells by mediators of the acute phase response. 184 31

The human hepatoma cell line, HepG2, secreted an activity that degrades platelet-activating factor (PAF) by the hydrolysis of the sn-2 acetyl group. This activity was Ca++ independent, inhibited by diisopropylfluorophosphate but not by p-bromophenacyl bromide, and resistant to treatment with trypsin or pronase. Separation of HepG2-conditioned medium by gel filtration disclosed that the activity was associated with lipoproteins. An antiserum against PAF acetylhydrolase immunoprecipitated this activity. It was not recognized by an antibody against lecithin:cholesterol acyltransferase (LCAT), which also is secreted by HepG2 cells. Therefore the phospholipase A2 activity of LCAT was excluded as a source of the observed activity. PAF added to the culture medium stimulated the secretion of the PAF-degrading activity by HepG2 cells, while lyso-PAF was inactive. Maximal stimulation was observed with 5 ng/ml PAF, which induced a fivefold increase. The presence of 5 ng/ml PAF, enhanced the secretion of [35S]methionine-labeled PAF acetylhydrolase and cycloheximide inhibited both the basal and PAF-stimulated secretion of the labeled enzyme. We conclude that HepG2 cells produce PAF acetylhydrolase. The liver may be a major source of plasma PAF acetylhydrolase, and PAF may induce the production of its inactivating enzyme by the liver.
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PMID:Platelet-activating factor (PAF) stimulates the production of PAF acetylhydrolase by the human hepatoma cell line, HepG2. 184 78

Neutral phospholipase A2 activity, which hydrolyzed phosphatidylcholine and phosphatidylethanolamine with the same efficiency, was identified in the nuclear matrix prepared from purified nuclei of rat ascites hepatoma cells (AH 7974). The enzyme activity was optimal at pH 7.0 and required Ca2+ absolutely. Concentrations of Ca2+ for a maximal and a half-maximal activation were 1.10(-2) and 1.10(-3) M, respectively, and little activity was detected at Ca2+ concentrations lower than 1.10(-5) M. Addition of acidic phospholipids markedly stimulated the enzyme activity, and further, lowered the minimum Ca2+ concentration required for activation. In particular, the polyphosphoionositides phosphatidylinositol 4-monophosphate and 4,5-diphosphate were most effective. These two polyphosphoinositides lowered the Ca2+ concentration required for half-maximal activation to 10(-5) M and dramatically stimulated the activity at that Ca2+ concentration (greater than 30-fold). The neutral phospholipase A2 activity such as characterized in the present study was very low in the other subcellular fractions including mitochondria, microsome, plasma membrane and cytosol.
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PMID:A novel phospholipase A2 associated with nuclear matrix: stimulation of the activity and modulation of the Ca2+ dependency by polyphosphoinositides. 253 88

The effects of tumour-promoting phorbol esters on the receptor-mediated endocytosis of insulin were investigated in the human hepatoma cell line HepG2. Treatment of these cells with the biologically active phorbol 12-O-tetradecanoylphorbol 13-acetate (TPA), but not with the non-tumour-promoting analogue 4 alpha-phorbol 12,13-didecanoate, resulted in dramatic morphological changes, which were accompanied by a 1.5-2.5-fold increase in specific 125I-insulin association with the cells at 37 degrees C. This increase in insulin binding was not observed when the binding reaction was performed at 4 degrees C. The potentiation of 125I-insulin association with TPA-treated cells at 37 degrees C could be completely accounted for by an increase in the intracellular pool of internalized insulin; there was no concomitant increase in cell-surface insulin binding. Dissociation studies showed that the enhanced internalization of insulin by cells after treatment with TPA resulted from a decrease in the rate of intracellular processing of the insulin after receptor-mediated endocytosis. The phorbol-ester-induced enhancement of internalized insulin in HepG2 cells was additive with the potentiation of endocytosed insulin induced by both the lysosomotropic reagent chloroquine and the ionophore monensin; this indicates that TPA affects the intracellular processing of the insulin receptor at a point other than those disrupted by either of these two reagents. The potentiation of insulin receptor internalization by tumour-promoting phorbol esters could be completely mimicked by treatment with phospholipase C, but not with phospholipase A, and partially mimicked by treatment with the synthetic diacylglycerol 1-oleoyl-2-acetylglycerol. By these criteria, the effects of phorbol esters on the insulin receptor in HepG2 cells appear to be mediated through protein kinase C. These results support the concept that the activation of protein kinase C by treatment with phorbol esters causes a perturbation of the insulin-receptor-mediated endocytotic pathway in HepG2 cells, reflected in a long-term decreased rate of dissociation of internalized insulin by the phorbol-ester-treated cells.
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PMID:Potentiation of specific association of insulin with HepG2 cells by phorbol esters. 353 1

This study identifies and partially characterizes an insulin-sensitive glycophospholipid in H35 hepatoma cells. The incorporation of [3H]glucosamine into cell lipids was investigated. A major labeled lipid was purified by sequential thin layer chromatography using first an acid followed by a basic solvent system. After hydrochloric acid hydrolysis and sugar analysis by thin layer chromatography, 80% of the radioactivity in the purified lipid was found to comigrate with glucosamine. H35 cells were prelabeled with [3H]glucosamine for either 4 or 24 h and treated with insulin causing a dose-dependent stimulation of turnover of the glycophospholipid which was detected within 1 min. The purified glycolipid was cleaved by nitrous acid deamination indicating that the glucosamine C-1 was linked to the lipid moiety through a glycosidic bond. [14C]Ethanolamine, [3H]inositol, and [3H]sorbitol were not incorporated into the purified glycolipid. The incorporation of various fatty acids into this glycolipid was also studied. [3H]Palmitate was found to be preferentially incorporated while myristic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and arachidonic acid were either not incorporated or incorporated less than 10% of palmitate. The purified glycolipid labeled with [3H]palmitate was cleaved by treatment with phospholipase A2 but was resistant to mild alkali hydrolysis suggesting the presence of a 1-hexadecyl,2-palmitoyl-glyceryl moiety in the purified lipid. Treatment of labeled glycophospholipid with phosphatidylinositol-specific phospholipase C from Staphylococcus aureus generated a compound migrating as 1-alkyl,2-acyl-glycerol and a polar head group with a size in the range from 800 to 3500. These findings coupled with the nitrous acid deamination demonstrate that glucosamine was covalently linked through a phosphodiester bond to the glyceryl moiety of the purified glycolipid. These findings suggest that insulin acts on this glycophospholipid by stimulating an insulin-sensitive phospholipase C. This unique glycophospholipid may play an important role in insulin action by serving as precursor of insulin-generated mediators.
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PMID:Identification of a novel insulin-sensitive glycophospholipid from H35 hepatoma cells. 354 86

The bidirectional surface transfer of free cholesterol (FC) between Fu5AH rat hepatoma cells and human high density lipoprotein (HDL) was studied. Cells and HDL were prelabeled with [4-14C]FC and [7-3H]FC, respectively. Influx and efflux of FC were measured simultaneously from the appearance of 3H counts in cells and 14C counts in medium. Results were analyzed by a computerized procedure which fitted sets of kinetic data to a model assuming that cell and HDL FC populations each formed a single homogeneous pool and that together the pools formed a closed system. This analysis yielded values for the first-order rate constants of FC influx and efflux (ki and ke), from which influx and efflux of FC mass (Fi and Fe) could be calculated. With normal HDL, the uptake and release of FC tracers conformed well to the above-described model; Fi and Fe were approximately equal, suggesting an exchange of FC between cells and HDL. HDL was depleted of phospholipid (PL) by treatment with either phospholipase A2 or heparin-releasable rat hepatic lipase, followed by incubation with bovine serum albumin. PL depletion of HDL had little or no effect on ki, but reduced ke, indicating that PL-deficient HDL is a relatively poor acceptor of cell cholesterol. The reduction in ke resulted in initial Fi greater than Fe and, thus, in net uptake of FC by the cells. This result explained previous results demonstrating net uptake of FC from PL-depleted HDL. In the presence of an inhibitor of acyl coenzyme A:cholesterol acyltransferase, the steady state distribution of FC mass between cells and HDL was accurately predicted by the ratio of rate constants for FC flux. This result provided additional validation for describing FC flux in terms of first-order rate constants and homogeneous cell and HDL FC pools.
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PMID:The bidirectional flux of cholesterol between cells and lipoproteins. Effects of phospholipid depletion of high density lipoprotein. 370 Mar 71

The objective of this study was to determine whether high density lipoproteins (HDL) that have been treated with hepatic lipase have an enhanced ability to deliver cholesterol to cells. Human HDL was incubated with rat hepatic lipase, reisolated, and subjected to compositional analysis. Approximately 28% of the HDL phosphatidylcholine was hydrolyzed by the hepatic lipase but no change was detected in the cholesterol or apoprotein content of the HDL compared to HDL incubated with heat-inactivated hepatic lipase. Cultured rat hepatoma cells exposed to hepatic lipase-modified HDL showed an increased uptake of HDL free cholesterol relative to cells exposed to control HDL. This increased delivery of HDL free cholesterol was demonstrated by both isotopic and mass determinations and it contributed to a 1.6-fold increase in total cellular cholesterol content relative to cells treated with control HDL. The free cholesterol delivered by the HDL is functionally available to the cell as evidenced by the conversion of radiolabeled free cholesterol to cholesteryl ester. The stimulation of free cholesterol delivery was dose-dependent up to a level of 100 micrograms of HDL free cholesterol/ml of extracellular medium, and was directly related to the extent of phosphatidylcholine hydrolysis. The enhanced cellular accumulation of HDL free cholesterol observed with hepatic lipase appears to be due to the phospholipase activity of this enzyme, since similar results were obtained with HDL that had been modified by snake venom phospholipase A2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hepatic lipase stimulates the uptake of high density lipoprotein cholesterol by hepatoma cells. 663 Dec 21

3M-KCl extracts of the hepatoma D23 contain antigens that inhibit the complement-dependent cytotoxicity for D23 hepatoma cells of serum from D23 tumour-bearing rats (D23 TBS). Inhibition was not due to a general anticomplementary activity of the extracts. Although a minor part (25%) of the protein of D23-KCl extract was insoluble in PBS, this part contained most of the inhibitory activity. Fractionation of the PBS-soluble material of the extract on Concanavalin A-Sepharose showed that the inhibitory activity did not bind to the lectin. Analysis of D23-KCl extracts on a Sepharose CL-4B column showed that the antigens involved in the cytotoxicity were heterogeneously distributed in the high-mol. wt region (greater than 200,000). Precipitation with 10% trichloroacetic acid (TCA) of D23 KCl extracts revealed that most of the antigenicity was insoluble in TCA. Heating of D23 KCl extracts at 100 degrees C did not affect the antigenicity. Enzyme treatment of D23 extra nuclear membranes (D23 ENP) revealed that the inhibitory activity was not sensitive to proteolytic digestion, while treatment with phospholipase A2, C or D abrogated partly the inhibitory activity. The lipid nature of the antigenicity was indicated by its solubility in organic solvents as chloroform or n-butanol.
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PMID:Tumour-associated antigens reacting with cytotoxic antibodies in serum of hepatoma-bearing rats. 729 8

A phospholipase A2 bound tightly to the particulate fractions of rat ascites hepatoma cells was purified approximately 13,000-fold with a reasonably high yield (34%) by extraction with sodium cholate, ammonium sulfate fractionation, solubilization with sodium dodecyl sulfate, column chromatographies on Sephadex G-150 in the presence of sodium dodecyl sulfate, and on DEAE-cellulose and CM-cellulose in the presence of Triton X-100. The enzyme has a unique substrate specificity; namely, it preferentially hydrolyzes phosphatidylethanolamine and, to a lesser degree, phosphatidylglycerol. However, it does not attack phosphatidylcholine, phosphatidic acid or cardiolipin in the present experimental conditions. The final preparation shows both phospholipase A2 and lysophospholipase L2 activities, but neither lysophospholipase L1 nor lipase activity. The purified enzyme has a rather broad pH optimum ranging from 7 to 9, requires Ca2+, and is resistant to heat-treatment at 95 degree C for 5 min.
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PMID:Purification and properties of a membrane-bound phospholipase A2 from rat ascites hepatoma 108A cells. 739 Sep 73


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