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)

Albumin carries fatty acids and has also been suggested to act as an antioxidant. In the present work, polyunsaturated fatty acids (linoleic, arachidonic, eicosapentaenoic and docosahexaenoic acids)--but not palmitic and oleic acid--inhibited growth of human hepatoma cells in low albumin concentration (0.5%). Growth inhibition by polyunsaturated fatty acids was prevented by albumin in a dose-related manner in the range 0.7-5.0%. Albumin also protected against growth inhibition following catabolism (by lipoprotein lipase) of very low density lipoproteins. Vitamin E strongly counteracted the inhibitory effect of polyunsaturated fatty acids. Vitamin E and albumin appeared to have additive effects in protecting against growth inhibition by polyunsaturated fatty acids. Indomethacin did not greatly modify the polyunsaturated fatty acids effect. Growth inhibition by polyunsaturated fatty acids, as well as the level of thiobarbituric acid reacting substances (a measure of lipid peroxidation) in growth media, increased with increasing number of fatty acids double bonds. Vitamin E and albumin prevented both thiobarbituric acid reacting substances formation and growth inhibition by polyunsaturated fatty acids. The results suggest that the concentrations of albumin and vitamin E in the incubation medium are essential when studying polyunsaturated fatty acids effects on cell growth.
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PMID:Growth inhibition of human hepatoma cells (HepG2) by polyunsaturated fatty acids. Protection by albumin and vitamin E. 131 55

Recently, it was shown that lipoprotein lipase (LPL) was produced in neonatal but not in adult rat liver. In an attempt to further define the mechanism involved in liver LPL expression, we identified a neonatal mouse hepatoma cell line, BWTG3, capable of producing LPL. The regulation of LPL expression by various extracellular stimuli was investigated in this cell line. Progesterone caused a rise in LPL production by BWTG3 cells. Other hormones tested, such as insulin, glucagon, adrenalin, testosterone, and thyroid hormone, had no effect on LPL production. The effects of progesterone on LPL production showed slow kinetics reaching a maximum 24 h after addition. Cotransfection of a progesterone receptor expression vector with a 5'-LPL-CAT reporter construct resulted in an induction of CAT activity, suggesting that the increase in LPL accumulation after progesterone was linked to transcriptional induction of the LPL gene. Stimuli causing an elevation of protein kinase A activity in the cells also increased LPL production. Three agents capable of elevating intracellular cAMP levels, i.e., forskolin, dBcAMP, and choleratoxin, caused an elevation of LPL production. The increase in LPL activity caused by forskolin and choleratoxin was paralleled by an elevation of LPL mRNA levels, while dBcAMP only induced a small elevation of LPL mRNA levels. The increase in LPL production was shown to be linked to the stimulation of the PKA signal transduction pathway and was apparently transmitted via the transcription factor CREB. No effect of the stimulation of protein kinase C or calcium/calmodulin-dependent kinase on LPL production was detected.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipoprotein lipase expression in undifferentiated hepatoma cells is regulated by progesterone and protein kinase A. 132 33

During lipolysis of chylomicron triacylglycerol by lipoprotein lipase, arachidonic acid (AA) esters are hydrolyzed at a slower rate than the predominant 16-18 carbon fatty acid esters. The further metabolism of the AA that is hereby enriched in the chylomicron remnant acylglycerols has not been investigated. In the present study, we examined the low density lipoprotein (LDL) dependent and independent metabolism of [14C]AA present in chylomicron remnants in the human hepatoma cell line Hep G2. Mesenteric duct cannulated rats were fed [14C]AA and [3H]cholesterol in corn oil, and the chyle obtained was injected intravenously into hepatectomized rats to form chylomicron remnants labeled with [14C]AA in the triacylglycerol (TG) and with 3H in the cholesteryl ester portion. The remnants were then incubated with Hep G2 cells. The uptake of [14C]AA within 2-4 h was similar to that of [3H]cholesteryl ester. After uptake into the cells, [14C]AA was preferentially incorporated into phospholipids, a high proportion being found in phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol. [14C]AA and [3H]cholesteryl ester uptake were influenced to similar extents by factors unknown to regulate the LDL receptor and by an anti-LDL receptor antibody. Addition of compactin thus increased the uptake of [14C]AA by 50% in 4 h and mevalonolactone decreased the uptake by 86%. Using an anti-LDL receptor antibody, 25.0% of [3H]cholesterol/cholesteryl ester and 37.7% of [14C]AA binding to the cells at 4 degrees C were blocked. There was no lipolysis of [14C]TG or [14C]diacylglycerol by lipase secreted into the medium during incubations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipoprotein receptor mediated metabolism of [14C]arachidonic acid labeled chylomicron remnants by Hep G2 cells. 133 5

Hypertriglyceridemia is common in the general population, but its mechanism is largely unknown. In previous work human apo CIII transgenic (HuCIIITg) mice were found to have elevated triglyceride levels. In this report, the mechanism for the hypertriglyceridemia was studied. Two different HuCIIITg mouse lines were used: a low expressor line with serum triglycerides of approximately 280 mg/dl, and a high expressor line with serum triglycerides of approximately 1,000 mg/dl. Elevated triglycerides were mainly in VLDL. VLDL particles were 1.5 times more triglyceride-rich in high expressor mice than in controls. The total amount of apo CIII (human and mouse) per VLDL particle was 2 and 2.5 times the normal amount in low and high expressors, respectively. Mouse apo E was decreased by 35 and 77% in low and high expressor mice, respectively. Under electron microscopy, VLDL particles from low and high expressor mice were found to have a larger mean diameter, 55.2 +/- 16.6 and 58.2 +/- 17.8 nm, respectively, compared with 51.0 +/- 13.4 nm from control mice. In in vivo studies, radiolabeled VLDL fractional catabolic rate (FCR) was reduced in low and high expressor mice to 2.58 and 0.77 pools/h, respectively, compared with 7.67 pools/h in controls, with no significant differences in the VLDL production rates. In an attempt to explain the reduced VLDL FCR in transgenic mice, tissue lipoprotein lipase (LPL) activity was determined in control and high expressor mice and no differences were observed. Also, VLDLs obtained from control and high expressor mice were found to be equally good substrates for purified LPL. Thus excess apo CIII in HuCIIITg mice does not cause reduced VLDL FCR by suppressing the amount of extractable LPL in tissues or making HuCIIITg VLDL a bad substrate for LPL. Tissue uptake of VLDL was studied in hepatoma cell cultures, and VLDL from transgenic mice was found to be taken up much more slowly than control VLDL (P < 0.0001), indicating that HuCIIITg VLDL is not well recognized by lipoprotein receptors. Additional in vivo studies with Triton-treated mice showed increased VLDL triglyceride, but not apo B, production in the HuCIIITg mice compared with controls. Tissue culture studies with primary hepatocytes showed a modest increase in triglyceride, but not apo B or total protein, secretion in high expressor mice compared with controls. In summary, hypertriglyceridemia in HuCIIITg mice appears to result primarily from decreased tissue uptake of triglyceride-rich particles from the circulation, which is most likely due to increased apo CIII and decreased apo E on VLDL particles. the HuCIIITg mouse appears to be a suitable animal model of primary familial hypertriglyceridemia, and these studies suggest a possible mechanism for this common lipoprotein disorder.
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PMID:Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles. 143 Feb 12

We showed previously that net secretory output of apolipoprotein B (apo B) from cultured human hepatoma cells (HepG2) is regulated by rapid reuptake of nascent lipoproteins before they have diffused away from the vicinity of the cells. We now sought to determine if the nascent lipoproteins could be remodeled to enhance or impede reuptake. We found that lipoprotein lipase (LpL), an enzyme that hydrolyzes lipoprotein triglyceride, reduced HepG2 output of apo B to one-quarter to one-half of control. The reduction was apparent during co-incubations as short as 2 h and as long as 24 h. Heparin, which blocks receptor-mediated binding of lipoproteins, abolished the effect of LpL on apo B output, without causing enzyme inhibition. To assess uptake directly, we prepared labeled nascent lipoproteins. LpL tripled the cellular uptake of labeled nascent lipoproteins, from 15.2% +/- 0.7% to 48.7% +/- 0.3% of the total applied to the cells. Cellular uptake of 125I-labeled anti-LDL receptor IgG was unaffected by LpL; thus, LpL enhanced reuptake by altering lipoproteins, not receptors. Because LpL is present in the space of Disse in the liver, we conclude that LpL may act on newly secreted lipoproteins to enhance reuptake in vivo. LpL deficiency would reduce local reuptake of apo B, which would appear as overproduction, thereby providing a mechanistic link between partial LpL deficiency and familial combined hyperlipidemia.
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PMID:Lipoprotein lipase modulates net secretory output of apolipoprotein B in vitro. A possible pathophysiologic explanation for familial combined hyperlipidemia. 191 80

Experiments were performed to evaluate the utility of a perfluorochemical emulsion as an artificial blood substitute for studies of lipoprotein metabolism in rats. Perfusing the liver of fed rats with perfluorochemical emulsion FC-34 at the same rate as a 20% red blood cell (RBC) perfusate, there was comparable oxygen uptake; however, there was a greater release of glucose and production of lactate than in RBC perfused livers. Under the stimulation of a low level of free fatty acid, there was less free fatty acid uptake and less triglyceride secretion in emulsion perfused livers. The lipoprotein secreted contained similar apoprotein, but there was a lower triglyceride to cholesterol ratio in the emulsion perfused liver. In addition to these moderate metabolic alterations, the uptake of radiolabeled chylomicron remnants by the perfused liver was almost completely suppressed when the perfluorochemical emulsion was used as an oxygen carrier. In vivo the presence of the perfluorochemical emulsion (5% of blood volume) decreased the rate of clearance of chylomicron remnants, beta-very-low-density lipoprotein (beta-VLDL) and cholesterol-rich high-density lipoprotein (HDLc), but not of low-density lipoprotein (LDL). In the presence of the emulsion, the degradation of 125I remnants, but not of [125I]LDL, by rat hepatoma cells was inhibited. The perfluorochemical emulsion did not inactivate lipoprotein lipase. The perfluorochemical emulsion did not change the triglyceride concentration or apoprotein composition of chylomicron remnants when they were incubated with the perfluorochemical emulsion at 37 degrees C for 1 hour and reisolated. The detergent used to solubilize the fluorocarbon FC-43, Pluronic F-68, did not affect the removal of chylomicron remnants in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of perfluorochemical artificial blood on lipoprotein metabolism in rats. 236 60

We have demonstrated that physiological concentrations of 17 beta-estradiol increase nuclear estrogen-specific binding sites in the human hepatoma cell line HepG2 7- to 10-fold and the rate of accumulation of secreted apolipoprotein C-II (apo-C-II), 2.5-fold (Tam, S-P., Archer, T. K., and Deeley, R. G. (1985) J. Biol. Chem. 260, 1670-1675). Apo-C-II is the major activator of lipoprotein lipase, an enzyme which plays a key role in lipoprotein catabolism. In order to define more precisely the mechanism by which estrogen influences apo-C-II production, we have synthesized a triacontanucleotide DNA probe that is complementary to apo-C-II mRNA. We have used the probe both in Northern hybridization experiments and in DNA excess titrations to quantify apo-C-II mRNA in hormonally treated HepG2 cells and various primate tissues. These studies revealed that: 1) the concentration of apo-C-II mRNA in HepG2 cells is comparable with that present in human liver; 2) treatment of the cells with low levels of estrogen results in a doubling of the apo-C-II mRNA concentration; 3) the apo-C-II mRNA concentration in monkey liver is 60- to 70-fold greater than in the intestine and 2.5-fold higher than in human liver.
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PMID:Apolipoprotein C-II mRNA levels in primate liver. Induction by estrogen in the human hepatocarcinoma cell line, HepG2. 298 68

The binding and metabolism of [3H]vitamin A-containing chylomicron (CM) remnants by the human hepatoma cell line HepG2 were studied. Mesenteric lymph chylomicrons were collected from [3H]retinol-fed rats and incubated with lipoprotein lipase to obtain CM remnants. At 4 degrees C, specific CM remnant binding was inhibited by an excess of unlabeled CM remnants. Specific binding predominated at low concentrations and approached saturation while total binding continued to increase over an extensive concentration range (0.45-32 microgram triglyceride/ml). CM remnant uptake at 37 degrees C was greater than that of CM and at least 70 times more efficient than the pinocytosis of sucrose. CM remnant binding increased with the extent of lipolysis. Addition of human apolipoprotein E enhanced both CM remnant and CM binding. After internalization, HepG2 cells hydrolyzed CM remnant-[3H]retinyl esters, and radiolabeled metabolites accumulated. As a function of the concentration of [3H]retinoid initially bound to cells, retinol and retinyl esters accumulated as the major cell-associated metabolites. In contrast, retinol was the major metabolite in the medium only at low retinoid concentrations; other more polar metabolites accumulated at higher concentrations (greater than 110 pmol retinoid/mg cell protein). The accumulation in the medium of labeled metabolites derived from CM remnant-retinoid was reduced when cells were preincubated in unlabeled retinol-supplemented media. The specific activity of retinol in the medium indicated that CM remnant-vitamin A had mixed with the cellular store prior to its secretion as retinol. These results indicate that HepG2 cells internalize CM remnants in part by specific binding sites, and that the metabolism of CM remnant-retinoids by the HepG2 cell involves retinyl ester hydrolysis and the secretion of retinol and other more polar metabolites. These processes were regulated in part by the concentration of retinoid delivered by the CM remnant and by the initial retinoid content of the cell.
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PMID:Chylomicron remnant-vitamin A metabolism by the human hepatoma cell line HepG2. 303 18

Factors leading to microsomal enzyme induction are associated with hypertriglyceridemia in man. Phenobarbital (PB) increases hepatic synthesis of triglyceride but lowers its serum concentration in rats due to increased postheparin plasma activities of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL); these changes are accompanied by increased activity of these lipolytic enzymes in adipose tissue and liver. The present work explores the cellular mechanisms whereby PB increases the tissue content of these enzymes, using primary cultures of rat liver hepatocytes and a continuous cell line of mouse fibroblasts (preadipocytes) that undergo differentiation into mature fat cells. Secretion and synthesis of HTGL in primary rat hepatocytes increased 50% with insulin; when PB was added with insulin, activity was enhanced an additional 50%. By contrast, insulin inhibited HTGL secretion from the well differentiated rat hepatoma cell line, FU-5-5, C8, and this inhibition was partly overcome by PB. These results suggest that different control mechanisms govern the synthesis and secretion of HTGL in normal rat liver cells and hepatoma. In cultured pre-adipocytes (3T3-F442A) insulin promoted differentiation when added to confluent cultures. PB (0.5 mM) resulted in marked enhancement of conversion of adipocytes characterized by a two- to threefold increase in extracellular LPL and a 10-fold increase in intracellular enzyme. These results suggest that PB promotes conversion of uncommitted cells into pre-adipocytes at an early stage in the differentiation of adipose tissue.
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PMID:Lipolytic enzymes as markers of induction and differentiation. 332 93

The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) is a cell-surface glycoprotein of 4525 amino acids that functions as a hepatic endocytosis receptor for several plasma proteins. These include alpha 2-macroglobulin-protease complexes, free plasminogen activators as well as plasminogen activators complexed with their inhibitors, and beta-migrating very low density lipoproteins complexed with either apolipoprotein E or lipoprotein lipase. In the current study we used human and rat hepatoma cell lines to demonstrate that LRP can mediate the degradation of tissue factor pathway inhibitor (TFPI), a Kunitz-type plasma serine protease inhibitor that regulates tissue factor-induced blood coagulation. The cellular degradation of 125I-labeled TFPI (125I-TFPI) was inhibited more than 80% both by antibodies directed against LRP and by the LRP-associated 39-kDa protein, a protein that inhibits the binding and/or cell-mediated degradation of all ligands by LRP. Using rat hepatoma cells, we report that at 4 degrees C, 125I-TFPI binds to approximately 2 x 10(6) sites per cell with an equilibrium dissociation constant of approximately 30 nM. 125I-TFPI binding to the cell surface is not inhibited by the 39-kDa protein. Taken together, our results suggest that TFPI binds to an as-yet-unidentified cell surface molecule. After binding, LRP mediates the cellular degradation of TFPI.
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PMID:The low density lipoprotein receptor-related protein mediates the cellular degradation of tissue factor pathway inhibitor. 751 57


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