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 effects of 3-substituted Delta8(14)-15-ketosterols--3beta-(2-hydroxyethoxy)-, 3beta-(2-propenyloxy)-, 3beta-[2(R,S),2,3-oxidopropyloxy]-, 3beta-[2(R,S),2,3-dihydroxypropyloxy]-, 3beta-(2-oxoethoxy)-, 3beta-[2(R,S),2-acetoxy-3-acetamidopropyloxy]-, and 3beta-[2(R,S), 2-hydroxy-3-acetamidopropyloxy]-5alpha-cholest-8(14)-en-15-o nes--on cholesterol metabolism were studied in human hepatoma Hep G2 cells. 3beta-(2-Propenyloxy)-, 3beta-(2-oxoethoxy)-, and 3beta-[2(R,S),2, 3-oxidopropyloxy]-5alpha-cholest-8(14)-en-15-ones inhibited cholesterol biosynthesis without any effect on triglyceride biosynthesis, while 3beta-[2(R,S),2-acetoxy-3-acetamidopropyloxy]- and 3beta-[2(R,S), 2-hydroxy-3-acetamidopropyloxy]-5alpha-cholest-8(14)-en-15-o nes inhibited both cholesterol biosynthesis and triglyceride biosynthesis at concentrations exceeding 10 microM. 3beta-[2(R,S),2, 3-Dihydroxypropyloxy]-5alpha-cholest-8(14)-en-15-one, effectively inhibiting cholesterol biosynthesis, was found also to be toxic in Hep G2 cells at micromolar concentrations. 3beta-[2(R,S),2, 3-Oxidopropyloxy]-5alpha-cholest-8(14)-en-15-one effectively inhibited cholesterol acylation. All the tested compounds decreased the HMG-CoA reductase mRNA level at concentrations exceeding 10 microM; however, they did not affect the LDL receptor mRNA level. Among the compounds tested, only 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one decreased the uptake and internalization of LDL-associated cholesteryl esters, being as effective as 25-hydroxycholesterol.
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PMID:Effect of 3-substituted Delta8(14)-15-ketosterols on cholesterol metabolism in hepatoma Hep G2 cells. 1023 1

Several clinical studies have shown that different types of non-steroidal anti-inflammatory drugs (NSAIDs) can reduce the cholesterol content of atherosclerotic blood vessels. The mechanism of this reduction is not established. One possibility is that NSAIDs affect low density lipoprotein (LDL) catabolism. In this study, we investigated the effect of the NSAIDs, indomethacin, flufenamic acid, ibuprofen, acetaminophen, and also acetylsalicylic acid on LDL binding, cell-association and degradation in cultured hepatoma HepG2 cells. LDL was labelled with 125I to study LDL catabolism. Furthermore, dextran sulphate, a substance that is known to release bound LDL from its receptors, was used to study LDL receptor activity. Reverse transcription-polymerase chain reaction was used to study the messenger RNA (mRNA) of LDL receptor. Our results show that flufenamic acid, indomethacin, and to a lesser extent ibuprofen, and acetaminophen increase LDL binding, cell-association, and degradation. Flufenamic acid was most potent and increased LDL catabolism by 50-70%, whereas acetylsalicylic acid had only a modest effect. Also, flufenamic acid and indomethacin were both found to increase the synthesis of mRNA of the LDL receptor with a subsequent increase of LDL receptor protein. We also investigated the effect of indomethacin on LDL binding in the presence of the 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase inhibitor, fluvastatin. We found that both indomethacin and fluvastatin had an additive up-regulatory effect on LDL receptor activity. In addition the effect of flufenamic acid on cell-associated LDL was examined in the presence of cyclosporine, which is known to decrease LDL catabolism. The results show that flufenamic acid can restore the inhibitory effect of cyclosporine. The study thus shows that NSAIDs enhance LDL catabolism due to increased synthesis of the mRNA for LDL receptor protein. This action might contribute to the lipid-lowering effect of NSAIDs.
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PMID:Enhancement of low density lipoprotein catabolism by non-steroidal anti-inflammatory drugs in cultured HepG2 cells. 1039 27

Recent therapeutic strategies for the treatment of familial hypercholesterolemia have been based on liver-directed gene transfer of a functional low-density lipoprotein (LDL) receptor cDNA under control of viral or strong housekeeping promoters. Strong viral promoters including cytomegalovirus, Rous sarcoma virus, and simian virus 40 promoters are commonly employed to reach significant physiological effects. These promoters mediate constitutive and nonphysiological overexpression in every transduced cell, while the endogenous LDL receptor expression is controlled by a complex feedback mechanism based on intracellular cholesterol concentration. To investigate intracellular consequences of persistent LDL receptor overexpression we constructed a recombinant adenovirus encoding the human LDL receptor under control of the Rous sarcoma virus promoter. The metabolic and morphological effects of LDL receptor expression were characterized by uptake experiments with human hepatoma cells using fluorescent and radiolabeled LDL. We observed that large amounts of LDL accumulate within LDL receptor transduced cells, which eventually lead to massive intracellular lipid deposition. Kinetic experiments with LDL-supplemented medium resulted in numerous crystal shaped structures in the cytosol of transduced cells as visualized by digital interference contrast optic within 60 min after LDL supplementation. Thin layer chromatography analyses of cellular lipids suggested these crystalline structures to be dependent on intracellular cholesterol and cholesterol ester levels. Mock-infected cells showed neither cholesterol lipid accumulation nor crystal formation. In conclusion, our data demonstrate that nonphysiological overexpression of the LDL receptor can cause massive lipid accumulation, which cannot be compensated by the hepatoma cell metabolism. This phenomenon may result in negative selection of LDL receptor overexpressing cells in vitro and in vivo.
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PMID:Nonphysiological overexpression of low-density lipoprotein receptors causes pathological intracellular lipid accumulation and the formation of cholesterol and cholesteryl ester crystals in vitro. 1060 9

Lifibrol (4-(4'-tert. butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) is a new hypocholesterolemic compound; it effectively lowers low density lipoprotein (LDL) cholesterol. We studied the effects of lifibrol on the cholesterol metabolism of cultured cells. In the hepatoma cell line HepG2, Lifibrol decreased the formation of sterols from [14C]-acetic acid by approximately 25%. Similar to lovastatin, lifibrol had no effect on the synthesis of sterols from [14C]-mevalonic acid. Lifibrol did not inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Instead, cholesterol synthesis inhibition by lifibrol was entirely accounted for by competitive inhibition of HMG-CoA synthase. Lifibrol enhanced the cellular binding, uptake, and degradation of LDL in cultured cells in a dose dependent fashion. The stimulation of LDL receptors was significantly stronger than expected from the effect of lifibrol on sterol synthesis. In parallel, lifibrol increased the amount of immunologically detectable receptor protein. Stimulation of LDL receptor mediated endocytosis was observed both in the presence and in the absence of cholesterol-containing lipoproteins. In the absence of an extracellular source of cholesterol, both lifibrol and lovastatin induced microsomal HMG-CoA reductase. Co-incubation with LDL was sufficient to suppress the lifibrol mediated increase in reductase activity, indicating that lifibrol does not affect the production of the non-sterol derivative(s) which are thought to regulate HMG-CoA reductase activity at the post-transcriptional level. Considered together, the data suggest that the hypolipidemic action of lifibrol may, at least in part, be mediated by sterol-independent stimulation of the LDL receptor pathway. A potential advantage of lifibrol is that therapeutic concentrations do not interfere with the production of mevalonate which is required not only to synthesize sterols but also as a precursor of electron transport moieties, glycoproteins and farnesylated proteins.
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PMID:The effects of lifibrol (K12.148) on the cholesterol metabolism of cultured cells: evidence for sterol independent stimulation of the LDL receptor pathway. 1105 1

The assembly and secretion of apo B100 containing lipoproteins (i.e., VLDL) by the liver and cholesterol metabolism are interrelated on several different levels and for several different physiologic reasons. Firstly, hepatic VLDL is the major precursor for LDL, which in the human is the major vehicle responsible for transporting cholesterol to peripheral tissues. Secondly, cholesterol is supplied to many tissues by a specific uptake of LDL via LDL receptor, which is expressed in a regulated manner by most mammalian tissues. Thirdly, the rate of hepatic cholesterol biosynthesis and metabolism to bile acids correlates with production of VLDL. This apparent coordinate expression of cholesterol biosynthetic/catabolic enzymes and hepatic VLDL assembly/secretion are mediated at least in part through the sterol response element binding protein (SREBP) transcription factor family. Their gene targets include a plethora of enzymes that regulate glycolysis, energy production, lipogenesis and cholesterol catabolism. Studies of hepatoma cells overexpressing CYP7A1, the rate-limiting enzyme controlling bile acid synthesis, show that as a result of increased mature SREBP1, there is a coordinate induction of lipogenesis and the assembly and secretion of VLDL. These and additional studies show that the bile acid synthetic pathway and the VLDL assembly/secretion pathway are coordinately linked through SREBP-dependent transcription. Based on studies showing that within the liver acinus, the expression of CYP7A1 is mainly in the pericentral region while HMG-CoA reductase is mainly periportal, we propose that a 'metabolic zonal segregation' plays an important role in coordinate regulation of cholesterol and VLDL metabolism. This putative 'metabolic zonal segregation' may provide segregation of metabolic functions which may be mutually antagonistic. For example, there may be physiologic states in which the bile acid synthetic pathway may compete with the VLDL assembly/secretion pathway for a limited amount of cholesterol. Metabolic antagonism (e.g., competition for cholesterol) may be avoided via inducing SREBP-mediated transcription. Adaptation of catabolic hepatocytes to accommodate the expression of VLDL assembly/secretion may occur in response to activation of SREBP-mediated transcription. Support for these is discussed.
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PMID:Cholesterol and hepatic lipoprotein assembly and secretion. 1111 Oct 91

The citrus flavonoids, naringenin and hesperetin, lower plasma cholesterol in vivo. However, the underlying mechanisms are not fully understood. The ability of these flavonoids to modulate apolipoprotein B (apoB) secretion and cellular cholesterol homeostasis was determined in the human hepatoma cell line, HepG2. apoB accumulation in the media decreased in a dose-dependent manner following 24-h incubations with naringenin (up to 82%, P < 0.00001) or hesperetin (up to 74%, P < 0.002). Decreased apoB secretion was associated with reduced cellular cholesteryl ester mass. Cholesterol esterification was decreased, dose-dependently, up to 84% (P < 0.0001) at flavonoid concentrations of 200 microM. Neither flavonoid demonstrated selective inhibition of either form of acyl CoA:cholesterol acyltransferase (ACAT) as determined using CHO cells stably transfected with either ACAT1 or ACAT2. However, in HepG2 cells, ACAT2 mRNA was selectively decreased (- 50%, P < 0.001) by both flavonoids, whereas ACAT1 mRNA was unaffected. In addition, naringenin and hesperetin decreased both the activity (- 20% to - 40%, P < 0.00004) and expression (- 30% to - 40%, P < 0.02) of microsomal triglyceride transfer protein (MTP). Both flavonoids caused a 5- to 7-fold increase (P < 0.02) in low density lipoprotein (LDL) receptor mRNA, which resulted in a 1.5- to 2-fold increase in uptake and degradation of (125)I-LDL. We conclude that both naringenin and hesperetin decrease the availability of lipids for assembly of apoB-containing lipoproteins, an effect mediated by 1) reduced activities of ACAT1 and ACAT2, 2) a selective decrease in ACAT2 expression, and 3) reduced MTP activity. Together with an enhanced expression of the LDL receptor, these mechanisms may explain the hypocholesterolemic properties of the citrus flavonoids.
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PMID:Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP. 1135 79

The effect of various 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on the induction of HMG-CoA reductase and low density lipoprotein (LDL) receptor mRNA were quantitatively determined in the cultured human hepatoma cell line Hep G2 by means of a ribonuclease protection assay. Lipophilic inhibitors including mevastatin, simvastatin, atorvastatin and NK-104 were able to increase the levels of mRNAs for HMG-CoA reductase and the LDL receptor, but the hydrophilic inhibitor pravastatin was not effective in Hep G2 cells as had previously been reported. The LDL receptor mRNA was induced by NK-104 most effectively between 0.1 to 10 microM among the lipophilic inhibitors, whereas the degrees of induction of HMG-CoA reductase mRNA by these inhibitors did not differ significantly from each other. When cells were treated with a 200-fold excess of the IC50 concentration of each inhibitor, NK-104 was able to induce LDL receptor mRNA most effectively. These results indicate that the effect of HMG-CoA reductase inhibitors on the upregulation of mRNA for reductase and LDL receptor are different from each other and among these lipophilic inhibitors. NK-104 is most effective in inducing LDL receptor mRNA in Hep G2 cells.
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PMID:Relative induction of mRNA for HMG CoA reductase and LDL receptor by five different HMG-CoA reductase inhibitors in cultured human cells. 1148 Apr 54

In a randomized, cross-over feeding trial involving 10 men with polygenic hypercholesterolemia, a control, Mediterranean-type cholesterol-lowering diet, and a diet of similar composition in which walnuts replaced approximately 35% of energy from unsaturated fat, were given for 6 weeks each. Compared with the control diet, the walnut diet reduced serum total and LDL cholesterol by 4.2% (P = 0.176), and 6.0% (P = 0.087), respectively. No changes were observed in HDL cholesterol, triglycerides, and apolipoprotein A-I levels or in the relative proportion of protein, triglycerides, phospholipids, and cholesteryl esters in LDL particles. The apolipoprotein B level declined in parallel with LDL cholesterol (6.0% reduction). Whole LDL, particularly the triglyceride fraction, was enriched in polyunsaturated fatty acids from walnuts (linoleic and alpha-linolenic acids). In comparison with LDL obtained during the control diet, LDL obtained during the walnut diet showed a 50% increase in association rates to the LDL receptor in human hepatoma HepG2 cells. LDL uptake by HepG2 cells was correlated with alpha-linolenic acid content of the triglyceride plus cholesteryl ester fractions of LDL particles (r(2) = 0.42, P < 0.05). Changes in the quantity and quality of LDL lipid fatty acids after a walnut-enriched diet facilitate receptor-mediated LDL clearance and may contribute to the cholesterol-lowering effect of walnut consumption.
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PMID:Walnut-enriched diet increases the association of LDL from hypercholesterolemic men with human HepG2 cells. 1173 80

Induction of low-density lipoprotein (LDL) receptor transcription in response to depletion of cellular sterols in animal cells is well established. The intracellular signal or signals involved in regulating this process, however, remain unknown. Using a specific inhibitor of protein kinase C (PKC), calphostin C, we show the requirement of this kinase in the induction process in human hepatoma HepG2 cells. Overexpression of PKC epsilon, but not PKC alpha, -gamma, -delta, or -zeta was found to dramatically induce (approximately 18-fold) LDL receptor promoter activity. Interestingly, PKC epsilon-mediated induction was found to be sterol resistant. To further establish that PKC epsilon is involved in the sterol regulation of LDL receptor gene transcription, endogenous PKC epsilon was specifically inhibited by transfection with antisense PKC epsilon phosphorothionate oligonucleotides. Antisense treatment decreased endogenous PKC epsilon protein levels and completely blocked induction of LDL receptor transcription following sterol depletion. PKC epsilon-induced LDL receptor transcription is independent of the extracellular signal-regulated kinase 1 and 2 (p42/44(MAPK)) cascade, because the MEK-1/2 inhibitor, PD98059 did not inhibit, even though it blocked p42/44(MAPK) activation. Finally, photoaffinity labeling studies showed an isoform-specific interaction between PKC epsilon and sterols, suggesting that sterols may directly modulate its function by hampering binding of activators. This was confirmed by PKC activity assays. Altogether, these results define a novel signaling pathway leading to induction of LDL receptor transcription following sterol depletion, and a model is proposed to account for a new function for PKC epsilon as part of a sterol-sensitive signal transduction pathway in hepatic cells.
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PMID:Critical role of diacylglycerol- and phospholipid-regulated protein kinase C epsilon in induction of low-density lipoprotein receptor transcription in response to depletion of cholesterol. 1199 13

The aim of this study was to determine the effects of vitamin E (alpha-tocopherol) on the low density lipoprotein (LDL) receptor, a cell surface protein which plays an important role in controlling blood cholesterol. Human HepG2 hepatoma cells were incubated for 24 hours with increasing amounts of alpha, delta, or gamma-tocopherol. The LDL receptor binding activity, protein and mRNA, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA, cell cholesterol and cell lathosterol were measured. The effect of alpha-tocopherol was biphasic. Up to a concentration of 50 microM, alpha-tocopherol progressively increased LDL receptor binding activity, protein and mRNA to maximum levels 2, 4 and 6-fold higher than control, respectively. The HMG-CoA reductase mRNA and the cell lathosterol concentration, indices of cholesterol synthesis, were also increased by 40% over control by treatment with 50 microM alpha-tocopherol. The cell cholesterol concentration was decreased by 20% compared to control at 50 microM alpha-tocopherol. However, at alpha-tocopherol concentrations higher than 50 microM, the LDL receptor binding activity, protein and mRNA, the HMG-CoA reductase mRNA and the cell lathosterol and cholesterol concentrations all returned to control levels. The biphasic effect on the LDL receptor was specific for alpha-tocopherol in that delta and gamma-tocopherol suppressed LDL receptor binding activity, protein and mRNA at all concentrations tested despite the cells incorporating similar amounts of the three homologues. In conclusion, alpha-tocopherol, exhibits a specific, concentration-dependent and biphasic "up then down" effect on the LDL receptor of HepG2 cells which appears to be at the level of gene transcription. Cholesterol synthesis appears to be similarly affected and the cell cholesterol concentration may mediate these effects.
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PMID:Alpha-tocopherol modulates the low density lipoprotein receptor of human HepG2 cells. 1277 5


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