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)

The plasma lecithin: cholesterol acyltransferase was determined in patients with various liver diseases and the relationship between this enzyme activity and the other liver function tests were studied including long term observations. Lecithin: cholesterol acyltransferase activity in fulminant hepatitis and liver cirrhosis showed a significant decrease in comparison with normal volunteers. Although the enzyme activity of hepatoma showed significant decrease, they were ascribed to the influence of concomitant liver cirrhosis. The enzyme activity showed insignificant changes in the acute and chronic hepatitis and alcoholic liver disease. Lecithin: cholesterol acyltransferase activity was correlated with the concentration of cholesterolester rather than with the ratio of esters to cholesterol. In addition, it was well correlated with pseudocholine esterase and serum albumin. The lecithin: cholesterol acyltransferase activity in the cases during follow-up period varied in good parallel with cholesterol-esters concentration and pseudocholine esterase in the cases with acute hepatitis; with serum albumin in the cases with liver cirrhosis. Furthermore, it varied inversely with SGPT in the cases with acute hepatitis. In a case with hepatoma, lecithin: cholesterol acyltransferase activity decreased more sharply than the cholesterolesters concentration and serum albumin immediately before death.
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PMID:Plasma lecithin: cholesterol acyltransferase activity in liver disease. 23 Sep 93

Regulation of low-density-lipoprotein-receptor activity by low-density lipoprotein (LDL), cholesteryl-ester-rich beta-migrating very-low-density lipoprotein (beta-VLDL) and non-lipoprotein cholesterol was investigated in the human hepatoma cell line Hep G2. Competition studies indicate that LDL and beta-VLDL are bound to the same recognition site, tentatively the LDL receptor. The regulatory response of the LDL receptor upon prolonged incubation with LDL or beta-VLDL was, however, markedly different. 22 h preincubation of Hep G2 cells with excess LDL caused a partial down regulation to 31% of the initial level of the high-affinity association of LDL and 26% of the high-affinity degradation of LDL, while with beta-VLDL a complete down regulation of the LDL-receptor activity is observed. Preincubation of Hep G2 cells with beta-VLDL for 22 h led to a fourfold increase in intracellular cholesterol esters and a twofold increase in acyl-coA:cholesterol acyltransferase activity. With LDL, the amount of intracellular cholesterol esters is increased 1.6-fold. The more effective down regulation of LDL receptors by beta-VLDL as compared to LDL can be explained by the more effective intracellular cholesterol delivery with beta-VLDL than with LDL. Preincubation of Hep G2 cells for 22 h with acetylated LDL hardly influenced the LDL-receptor activity. Non-lipoprotein cholesterol, however, caused a complete down regulation of LDL-receptor activity at even lower extracellular cholesterol concentrations than with beta-VLDL. The complete down regulation of LDL receptors by non-lipoprotein cholesterol is not accompanied by a significant increase in acyl-coA:cholesterol acyltransferase activity, while the intracellular cholesterol ester concentration is only increased 1.6-fold. It is suggested that the effectiveness of non-lipoprotein cholesterol to regulate LDL receptors is caused by its efficiency to reach the sterol regulatory site. The inability of LDL to down regulate its receptor completely can thus be explained by the inability of LDL to deliver cholesterol adequately at the intracellular regulatory site of the LDL receptor. The observed complete down regulation of the LDL receptor by beta-VLDL may be responsible for the cholesterol-rich-diet induced, complete down regulation of LDL-receptor-mediated clearance of LDL in vivo.
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PMID:Complete down-regulation of low-density-lipoprotein-receptor activity in the human hepatoma cell line Hep G2 by beta-migrating very-low-density lipoprotein and non-lipoprotein cholesterol. Different cellular regulatory pools of cholesterol. 131 43

The human hepatoma cell line, HepG2, was cultured with 25 OH cholesterol, a potent inhibitor of HMG-CoA reductase, in order to examine the effect of the oxysterol on apo E synthesis and secretion. Treatment of cells with oxysterol (2.5 microM) resulted in a greater than 90% inhibition of HMG-CoA reductase activity and a 3-fold reduction in its cognate mRNA level. However, apo E mRNA level and secretion were not affected after 24 h of drug treatment. This drug treatment was associated with a reduction in both cellular free and esterified cholesterol levels by 50% and 40%, respectively. Exposure of HepG2 cells to an ACAT inhibitor, the Sandoz compound (58-035) for 24 h, at a concentration of 5 micrograms/ml, resulted in a 30% increase and 70% decrease in the intracellular levels of free and esterified cholesterol, respectively. Under this regimen of drug treatment, the level of apo E mRNA was increased by approximately 70%, while HMG-CoA reductase mRNA level was decreased by 35%. When the cells were exposed to the combination of the ACAT inhibitor and 25 OH cholesterol, the cellular levels of free and esterified cholesterol were reduced by 30% and 80%, respectively. This combination of drugs had no effect on apo E mRNA; however, the level of HMG-CoA reductase mRNA was decreased by 3.5-fold. Taken together, the data suggested that reduction in the intracellular levels of either free or esterified cholesterol had no effect on apo E mRNA level. By contrast, a small increment in cellular free cholesterol content was associated with a significant induction in apo E mRNA level. Furthermore, 25 OH cholesterol caused a significant redistribution (50%) of apo E from the HDL fraction to the d greater than 1.21 g/ml infranatant. By using high performance liquid chromatography and molecular sieve columns, it was found that the appearance of a lipid-poor apo E particle was not an artifact of ultracentrifugation. This particle contained 85 wt% protein and 15 wt% of free cholesterol and phospholipid. The results suggested that a lipid-poor apo E particle was secreted by the HepG2 cells under certain circumstances.
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PMID:The effect of 25-hydroxycholesterol on the regulation of apolipoprotein E mRNA levels and secretion in the human hepatoma HepG2. 132 83

U-73482, a novel acylCoA:cholesterol acyltransferase (ACAT) inhibitor with systemic activity, has been evaluated for its effects on a variety of lipid metabolic parameters in the rat. The compound inhibits ACAT in vitro in cultured Fu5AH rat hepatoma cells and demonstrates systemic activity through inhibition of hepatic ACAT in rats receiving the drug orally. U-73482 also lowers plasma triglycerides at 40 mg/kg per day in the rat and elevates high density lipoprotein cholesterol (HDL-chol) in a dose-related fashion over the range of daily intakes of 0-40 mg/kg in the rat. Elevations in HDL-chol are followed by elevations in total plasma cholesterol in normal rats but the compound exerts hypocholesterolemic activity in cholesterol-fed rats and promotes clearance of stored hepatic sterol in rats pretreated with a hypercholesterolemic diet and then changed over to normal chow. The triglyceride-lowering and HDL-chol elevating effects of U-73482 coupled with its ability to promote tissue sterol clearance and block the hypercholesterolemic effects of dietary cholesterol in animals, suggests that the compound has potential as a therapeutic agent for treatment of lipid disorders in man.
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PMID:U-73482: a novel ACAT inhibitor that elevates HDL-cholesterol, lowers plasma triglyceride and facilitates hepatic cholesterol mobilization in the rat. 163 44

Chinese hamster ovary cells transfected with the human apolipoprotein A-I gene linked to the human metallothionein gene promoter region secrete large quantities of apolipoprotein A-I (7.1 +/- 0.4% total secreted protein) in the presence of zinc. Approx. 16% of the secreted apolipoprotein A-I is complexed with lipid and can be isolated ultracentrifugally at d less than or equal to 1.21 g/ml. The latter complexes are composed of discs and vesicles as judged by electron microscopy and can be further separated by column chromatography into three fractions: fraction I, mostly vesicles (60-260 nm) and large discs (18-20 nm diameter); fraction II, discs 14.2 +/- 2.6 nm diameter; and fraction III, nonresolvable by electron microscopy. The latter fraction is extremely lipid-poor (94% protein, 6% phospholipid); in contrast, the protein, phospholipid and unesterified cholesterol content for the other fractions are 43, 33 and 24%, respectively, for fraction I and 53, 33 and 14%, respectively, for fraction II. Fraction II particles contain three and four apolipoprotein A-Is per particle as determined by protein crosslinking while large structures in fraction I contain primarily six to seven apolipoprotein A-Is per particle. Following incubation with purified lecithin: cholesterol acyltransferase, discoidal particles were transformed into apparent spherical particles 12.9 +/- 3.4 nm diameter; this transformation coincided with 19-21% conversion of unesterified cholesterol to esterified cholesterol. The apolipoprotein A-I-lipid complexes isolated from Chinese hamster ovary cell media are similar to nascent HDL found in plasma of lecithin:cholesterol acyltransferase-deficient patients and those secreted by the human hepatoma line, Hep G2. The ability of the Chinese hamster ovary cell nascent HDL-like particles to undergo transformation in the presence of purified lecithin:cholesterol acyltransferase indicates that they are functional particles.
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PMID:Physical and chemical characteristics of apolipoprotein A-I-lipid complexes produced by Chinese hamster ovary cells transfected with the human apolipoprotein A-I gene. 212

The ability of high density lipoproteins (HDL) to induce the clearance of cholesteryl esters from cultured cells has been explored. Studies using the J774 mouse macrophage cell line showed that these cells are not stimulated to clear esterified cholesterol upon exposure to HDL. This was observed over a wide range of HDL concentrations (10 to 1000 micrograms/ml HDL protein), and the lack of stimulation was not influenced by a number of factors relating to the preparation of the HDL, such as HDL subfraction, varying extents of lecithin:cholesterol acyltransferase modification, or heparin-Sepharose chromatography to remove particles containing apo E. Neither the method of loading the cells with esterified cholesterol nor the physical state of the lipid droplets affected the inability of HDL to elicit esterified cholesterol clearance. In the presence of the acyl CoA:cholesterol acyltransferase inhibitor, Sandoz 58-035, where a high level of intracellular free cholesterol was generated, efflux of only a small fraction of the excess free cholesterol to HDL was observed. J774 cells were able to clear esterified cholesterol efficiently in the presence of cholesterol-free apolipoprotein HDL/phospholipid particles, indicating that the cells have the capacity to clear esterified cholesterol. Fu5AH hepatoma cells and P388.D1 mouse macrophage cells also failed to clear esterified cholesterol in response to HDL. In contrast, mouse peritoneal macrophages cleared esterified cholesterol efficiently to HDL, indicating that there are fundamental differences between mouse peritoneal macrophages and the other cells types studied in regard to cholesterol metabolism as influenced by HDL.
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PMID:Influence of high density lipoprotein on esterified cholesterol stores in macrophages and hepatoma cells. 229 43

To gain insight into the transport of sterol from lysosomes to the plasma membrane, we studied the efflux of lysosomal free cholesterol from intact Fu5AH rat hepatoma cells to high density lipoprotein (HDL) and other extracellular acceptors that promote sterol desorption from the plasma membrane. The procedures involved pulsing cells at 15 degrees C with low density lipoprotein that had been reconstituted with [3H]cholesteryl oleate and then incubating the cells at 37 degrees C in the presence of a sterol acceptor, while monitoring both the hydrolysis of [3H]cholesteryl oleate in lysosomes and the efflux of the resulting [3H]free cholesterol to the acceptor. After warming cells to 37 degrees C, rapid hydrolysis of [3H]cholesteryl oleate began after 10-20 min, and the lysosomally generated [3H]free cholesterol became available for efflux after an additional delay of 40-50 min. The kinetics of hydrolysis and the delay between hydrolysis and efflux were unchanged over a wide range of HDL3 concentrations (10-1000 micrograms of protein/ml), and with acceptors that do not interact with HDL-specific cell surface binding sites (phospholipid vesicles, dimethyl suberimidate cross-linked HDL). In addition, the delivery of lysosomal cholesterol to the plasma membrane was unaffected when cellular cholesterol content was elevated 2.6-fold above the normal control level, or when the activity of cellular acyl-coenzyme A/cholesterol acyltransferase (ACAT) was stimulated with exogenous oleic acid. We conclude that in the Fu5AH cell, a maximum of 40-50 min is required for the transport of cholesterol from lysosomes to the plasma membrane and that this transport is not regulated in response to either specific extracellular acceptors or the content of sterol in cells. The lack of effect of increased ACAT activity implies that the pathway for this transport does not involve passage of sterol through the rough endoplasmic reticulum, the subcellular location of ACAT.
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PMID:The efflux of lysosomal cholesterol from cells. 231 24

Cholesterol metabolism and its regulation are altered in hepatomas as compared to normal liver. We investigated parameters of cholesterol metabolism and their regulation in rats bearing the well-differentiated Morris hepatoma 9108. The numbers of membrane associated receptors recognizing chylomicron remnants, the lipoproteins that deliver dietary lipid to the liver, were substantially decreased in the 9108 tumor relative to the host liver. Cholesterol synthetic rates were 2-3-fold higher in the tumor, while the activity of 3-hydroxy-3-methylglutarylcoenzyme A reductase (EC 1.1.1.88), a rate-limiting enzyme for sterol synthesis, was elevated 6-14-fold. Although tumor free and esterified cholesterol contents were elevated, the activity of acylcoenzyme A:cholesterol acyltransferase (EC 2.3.1.26), the enzyme responsible for intracellular sterol esterification, was unchanged. Similar to the host liver, cholesterol synthesis and 3-hydroxy-3-methylglutarylcoenzyme A reductase were inhibited in the tumor when rats were fed a diet containing cholesterol, cholate and lard, and there was no effect on the numbers of chylomicron remnant receptors. Administering an intravenous bolus of very low density lipoproteins obtained from hypercholesterolemic rats caused an inhibition of tumor reductase activity, but had little effect on cholesterol content or cholesterol esterification. Thus, hepatoma 9108 expressed quantitative differences in cellular parameters involved in the uptake, metabolism, and synthesis of cholesterol and their susceptibility to regulation when compared with the host liver. These differences are best explained by changes in the hepatoma of multiple factors involved in the regulation of normal hepatic cholesterol metabolism.
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PMID:Regulation of cholesterol metabolism in a slow-growing hepatoma in vivo. 283 8

A human hepatoma cell line (HepG-2) was probed for the presence of lecithin: cholesterol acyltransferase (LCAT) using an antiserum to human plasma LCAT. Double immunodiffusion analysis using antiserum to human plasma LCAT revealed a single precipitin line in the sonicated cell homogenate. This precipitin line showed a reaction of identity with highly purified plasma LCAT. The presence of LCAT within the hepatoma cells was also confirmed by an immunofluorescence test. In contrast, the cell culture supernate showed a weak and inconsistent precipitin line. These data suggest that HepG-2 cells synthesize LCAT but secretion of the enzyme by these cells into the culture medium may be partially or totally impaired.
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PMID:Detection of lecithin: cholesterol acyltransferase (LCAT) in a human hepatoma cell line. 298 79

The regulation of the hepatic catabolism of normal human very-low-density lipoproteins (VLDL) was studied in human-derived hepatoma cell line HepG2. Concentration-dependent binding, uptake and degradation of 125I-labeled VLDL demonstrated that the hepatic removal of these particles proceeds through both the saturable and non-saturable processes. In the presence of excess unlabeled VLDL, the specific binding of 125-labeled VLDL accounted for 72% of the total binding. The preincubation of cells with unlabeled VLDL had little effect on the expression of receptors, but reductive methylation of VLDL particles reduced their binding capacity. Chloroquine and colchicine inhibited the degradation of 125I-labeled VLDL and increased their accumulation in the cell, indicating the involvement of lysosomes and microtubuli in this process. Receptor-mediated degradation was associated with a slight (13%) reduction in de novo sterol synthesis and had no significant effect on the cellular cholesterol esterification. Competition studies demonstrated the ability of unlabeled VLDL, low-density lipoproteins (LDL) and high-density lipoproteins (HDL) to effectively compete with 125I-labeled VLDL for binding to cells. No correlation was observed between the concentrations of apolipoproteins A-I, A-II, C-I, C-II and C-III of unlabeled lipoproteins and their inhibitory effect on 125I-labeled VLDL binding. When unlabeled VLDL, LDL and HDL were added at equal contents of either apolipoprotein B or apolipoprotein E, their inhibitory effect on the binding and uptake of 125I-labeled VLDL only correlated with apolipoprotein E. Under similar conditions, the ability of unlabeled VLDL, LDL and HDL to compete with 125I-labeled LDL for binding was a direct function of only their apolipoprotein B. These results demonstrate that in HepG2 cells, apolipoprotein E is the main recognition signal for receptor-mediated binding and degradation of VLDL particles, while apolipoprotein B functions as the sole recognition signal for the catabolism of LDL. Furthermore, the lack of any substantial regulation of beta-hydroxy-beta-methylglutaryl-CoA reductase and acyl-CoA:cholesterol acyltransferase activities subsequent to VLDL degradation, in contrast to that observed for LDL catabolism, suggests that, in HepG2 cells, the receptor-mediated removal of VLDL proceeds through processes independent of those involved in LDL catabolism.
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PMID:Studies on the binding and degradation of human very-low-density lipoproteins by human hepatoma cell line HepG2. 300 89


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