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)

We have investigated the effect of fatty acids on the rate of apolipoprotein B (apo B) secretion by human hepatoma cells (Hep G2). When Hep G2 cells were maintained in tissue culture flasks oleic acid up to 0.4 mM increased apo B secretion in a dose-dependent manner, whereas increases in triacylglycerol (TG) were smaller and dose dependency was less evident. In the absence of oleic acid, apo B accumulating in the tissue culture medium was predominantly in lipoproteins of higher density than very low density lipoproteins (VLDL). However, when the rate of secretion was stimulated with oleic acid the apo B-containing lipoproteins became lower in density. We postulated that there was a high rate of lipolysis of newly secreted VLDL by Hep G2 cells, which would account both for the relatively smaller effect of oleic acid on TG as opposed to apo B accumulating in the culture medium and the predominance of apo B in lipoproteins of a higher density than VLDL, which became less evident when VLDL secretory rates were stimulated by oleic acid. To test this hypothesis, cultured Hep G2 cells were transferred to columns containing Cytodex beads, permitting their continuous perfusion with culture medium so that newly secreted VLDL did not remain in contact with the cells. Apo B recovered from the perfusate was largely in VLDL range lipoproteins and the TG measured in the perfusate indicated that the true secretory rate of TG-rich lipoproteins was substantially higher than had been reflected by TG accumulating in culture medium left in contact with cells. Apo B measured in the culture medium of Hep G2 cells may thus be a better reflection of VLDL secretion, even though it is contained in higher density lipoproteins due to removal of TG by lipolysis. The effects of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) on apo B (apo B) secretion by Hep G2 cells maintained in tissue culture flasks were next investigated. SFA (0.4 mM), with the exception of stearic acid (C18:0), increased apo B secretion. Lauric acid (C12:0) increased apo B secretion by 32%, myristic acid (C14:0) by 41% (P<0.005), palmitic acid (C16:0) by 154% (P<0.025), and arachidic acid (C20:0) by 186% (P<0.005). The effect of MUFA (0.4 mM) was to increase apo B secretion, oleic acid (C18:1) by 239% ((P<0.0005) and palmitoleic acid (C16: 1) by 125% (P<0.005). Of the PUFA investigated, linolenic acid (C18:3) (0.4 mM) did not have any significant effect on apo B secretion, whereas linoleic acid (C18:2) (0.4mM) arachidonic acid (C20:4) (0.1 mM) and eicosapentaenoic acid (C20:5) (0.1 mM) caused significant increases of 164, 171 and 171%, respectively (P<0.005). The fatty acids studied increased intracellular TG and cholesteryl ester concentrations to varying extents. The increase in intracellular TG produced by the different fatty acids correlated with the rate of apo B secretion (r=0.6; P<0.05). In this human hepatoma cell line, with the exception of the saturated fatty acids, the rate of secretion of apo B-containing lipoproteins does not follow the same pattern as changes in circulating low density lipoprotein (LDL) concentrations reported with dietary manipulation in man. If our findings reflect the in vivo situation, we suggest that whilst the dietary effects of SFA on serum LDL may in part be determined by the hepatic apo B secretory rate, the effects of MUFA and PUFA must be largely mediated through a catabolic effect rather than an effect on hepatic secretion. The marked increase in apo B secretion with the more highly polyunsaturated fatty acids, such as eicosapentaenoic acid, may also explain why they do not lower circulating LDL, despite reports of their apparently favourable effect on LDL-receptor mediated clearance.
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PMID:The effects of fatty acids on apolipoprotein B secretion by human hepatoma cells (HEP G2). 1085 17

In this work, we have modified the fatty acid composition of Reuber H35 hepatoma cells by supplementation of the culture medium with a saturated (palmitic) or a polyunsaturated (docosahexaenoic) acid. These fatty acids were incorporated into total lipids and phospholipids of hepatoma cells. Palmitic acid readily increased the percentage of its monounsaturated derivative (16:1 n-7). When both fatty acids were supplemented at the same concentration, the percentage of docosahexaenoic acid in the total lipids and phospholipids of Reuber H35 cells increased more than that of palmitic acid. Although the levels of 16:0 increased, the addition of docosahexaenoic acid to the culture medium decreased the percentages of monoenoic acids. From our results, it can be concluded that palmitic and docosahexaenoic acids modify the fatty acid composition of Reuber H35 hepatoma cells. The profound changes induced by docosahexaenoic acid, especially those in the phospholipid fraction, may be of great interest given the main role of these components in the regulation of chemical and physical properties of biological membranes and/or membrane systems.
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PMID:Metabolism of palmitic and docosahexaenoic acids in Reuber H35 hepatoma cells. 1101 Nov 36

We have investigated the effects of arachidonic and palmitic acids in isolated rat liver mitochondria and in rat hepatoma MH1C1 cells. We show that both compounds induce the mitochondrial permeability transition (PT). At variance from palmitic acid, however, arachidonic acid causes a PT at concentrations that do not cause PT-independent depolarization or respiratory inhibition, suggesting a specific effect on the PT pore. When added to intact MH1C1 cells, arachidonic acid but not palmitic acid caused a mitochondrial PT in situ that was accompanied by cytochrome c release and rapidly followed by cell death. All these effects of arachidonic acid could be prevented by cyclosporin A but not by the phospholipase A(2) inhibitor aristolochic acid. In contrast, tumor necrosis factor alpha caused phospholipid hydrolysis, induction of the PT, cytochrome c release, and cell death that could be inhibited by both cyclosporin A and aristolochic acid. These findings suggest that arachidonic acid produced by cytosolic phospholipase A(2) may be a mediator of tumor necrosis factor alpha cytotoxicity in situ through induction of the mitochondrial PT.
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PMID:Arachidonic acid causes cell death through the mitochondrial permeability transition. Implications for tumor necrosis factor-alpha aopototic signaling. 1113 37

We investigated the growth inhibitory effect of conjugated linoleic acid (CLA) on HepG2 (human hepatoma cell line), exploring whether the inhibitory action occurs via lipid peroxidation in the cells. When the cells were incubated up to 72 h with 5-40 microM of CLA (a mixture of 9c,11t-18:2 and 10t,12c-18:2), cell proliferation was clearly inhibited in a dose and time dependent manner but such an inhibition was not confirmed with linoleic acid (LA). In order to evaluate the possible contribution of lipid peroxidation exerted by CLA to cell growth inhibition, alpha-tocopherol (5-20 microM) and BHT (1-10 microM) as potent antioxidants were added to the medium with CLA (20 microM), which did not restore cell growth at all. Furthermore, after 72 h incubation, the membranous phospholipid hydroperoxide formation in the CLA-supplemented cells was suppressed respectively to 25% and 50% of that in LA-supplemented cells and control cells. No difference was observed by a conventional lipid peroxide assay, the TBA test, between CLA-supplemented cells and LA-supplemented cells. Although the cellular lipid peroxidation was not stimulated, lipid contents (triacylglycerol, total cholesterol and free cholesterol) and fatty acid contents (palmitic acid, palmitoleic acid and stearic acid) markedly increased in CLA-supplemented cells compared with LA-supplemented and control cells. Moreover, supplementation with 20 microM LA and 20 microM arachidonic acid profoundly interfered with the inhibitory effect of CLA in HepG2. These results suggest that the growth inhibitory effect of CLA on HepG2 is due to changes in fatty acid metabolism but not to lipid peroxidation.
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PMID:The growth inhibitory effect of conjugated linoleic acid on a human hepatoma cell line, HepG2, is induced by a change in fatty acid metabolism, but not the facilitation of lipid peroxidation in the cells. 1123 19

Overexpression of acyl-CoA binding protein (ACBP) was induced in a rat hepatoma cell line (McA-RH 7777) by stable integration of rat ACBP cDNA. The transfected cells (ACBP-27) had 3.5-fold higher concentrations of ACBP than control cells (14 vs. 4 ng/microg DNA). Both ACBP-27 and control cells were cultured in the presence of various concentrations of radiolabeled palmitic acid; and the effects of ACBP on lipogenesis and beta-oxidation were studied. Incubation of the cells with 100 microM palmitic acid resulted in 42% greater incorporation of the fatty acid in ACBP-27 cells as compared to that in the control cells. This increased incorporation of the fatty acid was observed predominantly in the triglyceride fraction. Higher concentrations of palmitic acid (200 to 400 microM) were associated with a significant decrease in the production of 14CO2 in the ACBP-27 cell line than in the control cells, while lower concentrations had no effect. Our data suggest a role for ACBP in the partitioning of fatty acids between esterification reactions leading to the formation of neutral lipids and beta-oxidation. ACBP may play a regulatory role by influencing this important branch point in intermediary lipid metabolism.
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PMID:Overexpression of acyl-coA binding protein and its effects on the flux of free fatty acids in McA-RH 7777 cells. 1148 63

Our recent published studies suggest that angiotensin II (AII), generated and retained intracellularly, enhances growth of H4-II-E-C3 rat hepatoma cells, an average of 33%. Proliferation conferred by introduction of a plasmid [ Ang(-S)Exp/pSVL ] encoding a signal sequence-depleted angiotensinogen [Ang(-S)Exp] into these cells (which we have shown possess ACE and renin mRNAs) is mediated, at least in part, by enhanced PDGF-A chain mRNA production and protein secretion. The mitogenic effect is inhibited by losartan suggesting that it involves AII interaction with an AT(1)-like receptor. Introduction of anti-AII antibodies into the medium of these transfected cells has no effect upon growth of the cells, suggesting that AII is retained by the cells and that intracellular AII is growth stimulatory. In the present study, we sought to further characterize the intracellular localization and mode of action of Ang(-S)Exp. Consistent with our expectations, we now show that a fusion product of Ang(-S)Exp with green fluorescent protein [Ang(-S)Exp/EGFP], generated from an expression plasmid, is abundant and primarily cytoplasmic. Wild-type angiotensinogen/EGFP, in contrast, is only detectable following a cold-block (which acts to enhance folding-kinetics and slow secretion) and is largely restricted to the secretory pathway. We further show, using semi-quantitative RT/PCR that the long isoform of PDGF mRNA is elevated in Ang(-S)Exp transfected cells and in AII-treated naive cells but not in losartan-treated Ang(-S)Exp transfected cells. We identify C-terminal amidation recognition sites within the long-form protein (that are not present in the short-form) and show that these cells possess PAM (amidating enzyme precursor) and carboxypeptidase E mRNAs (the corresponding proteins of which are sufficient for amidation). Inhibitors of amidation inhibit growth of naive and Ang(-S)Cntr/ pSVL -transfected cells (2.6-fold for phenylbutenoic acid and 3.5-fold for disulfiram treatment) but more profoundly inhibit growth of Ang(-S)Exp/pSVL -transfected cells (6.7-fold for phenylbutenoic acid and 13-fold for disulfiram). In conclusion, these data confirm that signal sequence-depleted Ang(-S)Exp is retained within cells and is largely cytoplasmic. Because C-terminal amidation is absolutely required for full biological potency of a number of peptide hormones (including oxytocin, gastrin and calcitonin), we postulate that growth effects of both intracellular AII and exogenous AII can be conferred by PDGF long-form, possibly through an amidation-dependent mechanism.
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PMID:Intracellular angiotensin II increases the long isoform of PDGF mRNA in rat hepatoma cells. 1243 51

We investigated the effects of different fatty acids (FAs) or with different degrees of unsaturation on cytochrome P450 2E1 (CYP2E1) induction and protein kinase C (PKC) activity in human hepatoma HepG2 cells. As the degree of unsaturation increased, the cell survival rate decreased for FAs with 18 carbons, but linolenic acid (LNA) or docosahexaenoic acid (DHA) groups were similar even through they have different degrees of unsaturation. Treatment with palmitic acid (PA), oleic acid (OA), linoleic acid (LA), LNA, and DHA resulted in respective cellular FA concentrations of C16:0 (43.1%), C18:1 (18.5%), C18:2 (7.4%), LNA (2.85%), and C22:6 (3.13%), which was highest for the FA that was used as the treatment, indicating that their incorporation within the cell is directly proportional to treatment. After 2 hours of cultivation, the lipid peroxide (LPO) in the DHA group increased 600% compared with control, and was much higher than in the groups treated with the other FAs, with LNA > LA > OA > PA. CYP2E1 induction increased with greater effect as the degree of unsaturation of OA, LA, and DHA increased. PA did not affect PKC activity, but DHA treatment increased PKC activity the most. The effects of LNA and LA were similar, but less than that of DHA, and that of OA was lower still, indicating that activity of PKC is proportional to the degree of unsaturation, and not the configuration of the FA. Increased plasma membrane concentrations of n-3 FA, such as DHA, might exert regulatory effects on PKC by increasing membrane fluidity, causing changes in CYP2E1, elevating levels of LPO, or producing oxidative stress.
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PMID:Differential effects of dietary fatty acids on the regulation of CYP2E1 and protein kinase C in human hepatoma HepG2 cells. 1529 68

Cytosolic liver fatty acid binding protein (L-FABP) is involved in many intracellular functions including cellular mitogenesis. We investigated the role of L-FABP and the plasma membrane liver fatty acid binding proteins (L-FABP(pm)) in the modulation of hepatoma growth and proliferation, hypothesizing that agents that affect either the content of, or ligand binding to, L-FABP would affect hepatocellular mitogenesis. L-FABP expressing 1548-rat hepatoma cells were treated with 0.5 microM dexamethasone or 500 microM clofibrate for 4 days to downregulate and upregulate L-FABP expression, respectively. The competitive inhibitor 2-bromopalmitate (BrPA, 600 microM) was used to inhibit ligand binding to L-FABP. The peripherally present plasma membrane fatty acid transporter was inactivated by treating cells with 1:50 rabbit antisera (FABP-Ab) raised against L-FABP. Western blot analysis was used to monitor L-FABP levels while [(3)H]-thymidine incorporation and growth curves were used to monitor hepatocellular proliferation. [(3)H]-Palmitate clearance studies were performed using monolayer cultures. Palmitate clearance in dexamethasone-, BrPA- and FABP-Ab-treated cells was significantly reduced when compared with control (P < 0.05), while clofibrate treatment moderately increased the rate. [(3)H]-Thymidine incorporation by dexamethasone- and BrPA-treated cells was significantly lower than control (P < 0.05), suggesting that hepatocellular proliferation was inhibited. Clofibrate treatment did not statistically affect growth rate. Lowering L-FABP using dexamethasone or interfering with its activity using BrPA significantly affected hepatocellular proliferation. This may be due to the non-availability of long-chain fatty acids or other intracellular mediators that are transported by L-FABP to the nucleus.
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PMID:Effect of dexamethasone, 2-bromopalmitate and clofibrate on L-FABP mediated hepatoma proliferation. 1532 84

The aims of this study were to obtain concentrated pinolenic acid (5,9,12-18:3) from dietary Korean pine (Pinus koraiensis) nut oil by urea complexation and to investigate its cholesterol-lowering effect on the LDL-receptor activity of human hepatoma HepG2 cells. Pine nut oil was hydrolyzed to provide a low-pinolenic acid-containing FA extract (LPAFAE), followed by crystallization with different ratios of urea in ethanol (EtOH) or methanol (MeOH) as a solvent to produce a high-pinolenic acid-containing FA extract (HPAFAE). The profiles of HPAFAE obtained by urea complexation showed different FA compositions compared with LPAFAE. The long-chain saturated FA palmitic acid (16:0) and stearic acid (18:0) were decreased with urea/FA ratios (UFR) of 1:1 (UFR1), 2:1 (UFR2), and 3:1 (UFR3). Linoleic acid (9,12-18:2) was increased 1.3 times with UFR2 in EtOH, and linolenic acid (9,12,15-18:3) was increased 1.5 times with UFR3 in MeOH after crystallization. The crystallization with UFR3 in EtOH provided the highest concentration of pinolenic acid, which was elevated by 3.2-fold from 14.1 to 45.1%, whereas that of linoleic acid (9,12-18:2) was not changed, and that of oleic acid (9-18:1) was decreased 7.2-fold. Treatment of HepG2 cells with HPAFE resulted in significantly higher internalization of 3,3'-dioctadecylindocarbocyanine-LDL (47.0 +/- 0.15) as compared with treatment with LPAFAE (25.6 +/- 0.36) (P< 0.05). Thus, we demonstrate a method for the concentration of pinolenic acid and suggest that this concentrate may have LDL-lowering properties by enhancing hepatic LDL uptake.
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PMID:Selective increase in pinolenic acid (all-cis-5,9,12-18:3) in Korean pine nut oil by crystallization and its effect on LDL-receptor activity. 1535 26

Fatty acids and glucose are strong modulators of the expression of glucose-6-phosphatase (Glc-6-Pase), an enzyme that plays a key role in glucose homeostasis. PUFA inhibit, whereas SFA and monounsaturated fatty acids induce the expression of the Glc-6-Pase gene. Palmitate and oleate are the most abundant fatty acid species in circulation during food deprivation in mammals. Although dietary fats have been shown to modulate the expression of genes involved in both lipid and carbohydrate metabolism in liver, little is known regarding the molecular mechanism of transcriptional response of the Glc-6-Pase gene to long-chain fatty acids. Using H4IIE hepatoma cells and hepatocytes from adult rats, we investigated the mechanism of the induction of this gene by palmitate and oleate. Both of these fatty acids stimulated Glc-6-Pase gene transcription but did not affect the stability of its mRNA. In transient transfection assays, transcription from the Glc-6-Pase gene promoter was markedly enhanced by both palmitate and oleate but not by arachidonate. Chromatin immunoprecipitation analysis was used to show that palmitate induced the recruitment of an array of transcription factors viz hepatic nuclear factor(NF)-4alpha, CAAT/enhancer binding proteinbeta, PPARalpha, chicken ovalbumin upstream promoter transcription factor (COUP-TF), cAMP regulatory element binding protein, and NF-kappaB to this gene promoter. Although it is presently unclear how these various transcription factors interact at this promoter, the data are consistent with the view that multiple regulatory elements in the Glc-6-Pase gene promoter are responsible for the modulation of gene transcription by fatty acids.
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PMID:Several transcription factors are recruited to the glucose-6-phosphatase gene promoter in response to palmitate in rat hepatocytes and H4IIE cells. 1731 39


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