UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fenofibrate and other fibrate derivatives are commonly used to treat hyperlipidemia. It is not yet clear how they exert their modulatory effects on plasma lipoproteins. To investigate whether these drugs act on the liver to primarily inhibit very low density lipoprotein production, we utilized the highly differentiated human hepatoma cell line, Hep G2. At concentrations greater than 15 micrograms/mL, fenofibrate caused a 30% decrease in secreted apolipoprotein B (apo B) after 4 days of treatment. Pulse-chase studies demonstrated that this was not due to inhibition of apo B synthesis. Triglyceride synthesis by fenofibrate-treated Hep G2 cells was decreased by 30%, and the amount secreted into the medium was reduced by 50%. At a low concentration of drug (5 micrograms/mL), triglyceride secretion was reduced markedly while apo B secretion remained unchanged. Thus, apo B secretion is less sensitive to fenofibrate than the synthesis and secretion of triglyceride, and may be secondary to changes in the latter. Fenofibrate has also been shown to raise plasma high density lipoprotein concentrations. We found that low concentrations of fenofibrate caused a 20-101% increase in secreted apolipoprotein AI (apo AI), and pulse-chase immunoprecipitation studies showed that this was due to an increase in apo AI synthesis. Fenofibrate was compared to clofibrate to investigate whether their relative effects on lipoprotein production in Hep G2 cells were comparable to their relative effects on plasma lipoproteins. Both fibrates decreased the secretion of apo B to the same extent, but only fenofibrate increased apo AI secretion. Fenofibrate was more effective than clofibrate in inhibiting the secretion of lipids by these cells. Thus, the known effects of fenofibrate on plasma lipoproteins can be attributed to its direct modulation of lipoprotein synthesis in the liver cell. Hep G2 cells may thus be useful in testing the relative efficacy of fibric acid derivatives in vitro.
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PMID:Modulation of lipoprotein production in Hep G2 cells by fenofibrate and clofibrate. 131 85

Apolipoprotein CIII (apoCIII), a lipid-binding protein involved in the transport of triglycerides and cholesterol in the plasma, is synthesized primarily in the liver and the intestine. A cis-acting regulatory element, C3P, located at -90 to -66 upstream from the apoCIII gene transcriptional start site (+1), is necessary for maximal expression of the apoCIII gene in human hepatoma (HepG2) and intestinal carcinoma (Caco2) cells. This report shows that three members of the steroid receptor superfamily of transcription factors, hepatocyte nuclear factor 4 (HNF-4), apolipoprotein AI regulatory protein 1 (ARP-1), and Ear3/COUP-TF, act at the C3P site. HNF-4 activates apoCIII gene expression in HepG2 and Caco2 cells, while ARP-1 and Ear3/COUP-TF repress its expression in the same cells. HNF-4 activation is abolished by increasing amounts of ARP-1 or Ear3/COUP-TF, and repression by ARP-1 or Ear3/COUP-TF is alleviated by increasing amounts of HNF-4. HNF-4 and ARP-1 bind with similar affinities to the C3P site, suggesting that their opposing transcriptional effects may be mediated by direct competition for DNA binding. HNF-4 and ARP-1 mRNAs are present within the same cells in the liver and intestine, and protein extracts from hepatic tissue, HepG2, and Caco2 cells contain significantly more HNF-4 than ARP-1 or Ear3/COUP-TF binding activities. These findings suggest that the transcription of the apoCIII gene in vivo is dependent, at least in part, upon the intracellular balance of these positive and negative regulatory factors.
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PMID:Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells. 131 68

A previous study in rats showed that even though probucol substantially lowers high density lipoprotein (HDL) levels, near-normal mass transport of HDL cholesterol esters (CE) to the liver is maintained by the induction of "selective" (direct) uptake of HDL CE. The present study describes a parallel result in cultured Hep G2 human hepatoma cells. Cells were preincubated in the presence or absence of probucol before measuring the uptake of doubly labeled HDL3 in the absence of probucol. Preincubation with probucol decreased the uptake of HDL3 particles (iodine-125-labeled N-methyltyramine cellobiose-apolipoprotein [125I-NMTC-apo] A-I uptake) but increased the uptake of [3H]cholesteryl oleyl ether in excess of 125I-NMTC-apo A-I (i.e., selective uptake) in a dose-dependent fashion. The reversibly cell-associated pool of CE tracer, a precursor for selective uptake, enlarged on probucol treatment, but the increase was not in proportion to the increase in selective uptake. HDL3 particle uptake decreased on probucol treatment. The decrease was evident after less than 20 minutes of probucol exposure and was maximal after 6 hours; in contrast, HDL3 CE selective uptake increased only after greater than 13 hours and had not reached a plateau after 20 hours. Thus, effects on particle uptake and selective uptake were dissociated in time.
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PMID:Probucol increases the selective uptake of HDL cholesterol esters by Hep G2 human hepatoma cells. 131 37

The gene coding for apolipoprotein AI (apoAI), a lipid binding protein involved in the transport of cholesterol and other lipids in the plasma, is expressed in mammals predominantly in the liver and the intestine. Liver-specific expression is controlled by synergistic interactions between transcription factors bound to three separate sites, sites A (-214 to -192), B (-169 to -146), and C (-134 to -119), within a powerful liver-specific enhancer located between nucleotides -222 and -110 upstream of the apoAI gene transcription start site (+1). Previous studies in our laboratory have shown that ARP-1, a member of the nuclear receptor superfamily whose ligand is unknown (orphan receptor), binds to site A and represses transcription of the apoAI gene in liver cells. In a more recent series of experiments, we found that site A is a retinoic acid (RA) response element that responds preferentially to the recently identified RA-responsive receptor RXR alpha over the previously characterized RA receptors RAR alpha and RAR beta. In this study we investigated the combined effects of ARP-1 and RXR alpha on apoAI gene expression in liver cells. Transient transfection assays showed that site A is necessary and sufficient for RXR alpha-mediated transactivation of the apoAI gene basal promoter in human hepatoma HepG2 cells in the presence of RA and that this transactivation is abolished by increasing amounts of cotransfected ARP-1. Electrophoretic mobility shift assays and subsequent Scatchard analysis of the data revealed that ARP-1 and RXR alpha bind to site A with similar affinities. These assays also revealed that ARP-1 and RXR alpha bind to site A as heterodimers with an affinity approximately 10 times greater than that of either ARP-1 or RXR alpha alone. Further transfection assays in HepG2 cells, using as a reporter a construct containing the apoAI gene basal promoter and its upstream regulatory elements (including site A) in their natural context, revealed that RXR alpha has very little effect on the levels of expression regardless of the presence or absence of RA. However, while ARP-1 alone or ARP-1 and RXR alpha together dramatically repress expression in the absence of RA, the repression by ARP-1 and RXR alpha together, but not ARP-1 alone, is almost completely alleviated in the presence of RA. These results indicate that transcriptional repression by ARP-1 sensitizes apoAI gene responsiveness to RXR alpha and RA and suggest that the magnitude of this responsiveness is regulated by the intracellular ratio of ARP-1 to RXR alpha. These observations raise the possibility that transcriptional repression is a general mechanism for switching gene transcription between alternative transcription activation pathways.
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PMID:Repression by ARP-1 sensitizes apolipoprotein AI gene responsiveness to RXR alpha and retinoic acid. 132 32

Estrogen regulates the expression of the yolk protein genes in the chicken liver during periods of egg laying. While all five of these genes, vitellogenins I, II, and III, very low density apolipoprotein II (apo VLDLII), and apolipoprotein B, respond to estrogen, individual controls are superimposed on their coordinate regulation with respect to the kinetics of induction, magnitude of response, and developmental expression. The estrogen-responsive Leghorn strain M hepatoma (LMH) cell line provides a model system for studying the molecular basis of the similarities and differences in the regulation of these genes. The apoVLDLII gene is regulated by estrogen in LMH cells in an appropriate time- and dose-dependent manner. Regulatory regions of the apoVLDLII gene have been identified by transient transfection studies in LMH cells. All four of the sequences previously shown to bind protein between the TAATA motif at -26 and proximal estrogen response element at -171 are essential in regulation of the apoVLDLII gene. Mutation of any single binding region reduces expression by more than 80%, indicating cooperative interactions of proteins across the entire region. While these sequences will direct assembly of a functional transcription complex, we demonstrate that addition of the first intron of the apoVLDLII gene to the promoter construct results in a 4-fold increase in estrogen-dependent expression following transient transfection into LMH cells. Results of deletion analyses indicate that two distinct regions of the intron contribute to this regulation.
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PMID:Functional analysis of regulatory regions upstream and in the first intron of the estrogen-responsive chicken very low density apolipoprotein II gene. 137 8

The induction of rat hepatic mRNA S11 by L-T3 (T3) is a useful model for studying the mechanisms of thyroid hormone action. Although numerous reports have examined the response of mRNA S11 to various physiological and hormonal manipulations, the role of S11 protein in cellular metabolism remains unknown. In this study we show that mRNA S11 is abundantly expressed and regulated by T3 only in liver and small intestine. High levels of the mRNA are present at birth, but drop sharply between 30-60 days of age. These and other features of the S11 gene product were similar to those of rat apolipoprotein-A1 (Apo-A1). The sequence of S11 cDNA was identical to a portion of the Apo-A1 mRNA, thus confirming identity of the S11 mRNA. To examine whether DNA sequences immediately adjacent to the transcription start site mediate the effects of thyroid hormone, we measured the activity of an Apo-A1 gene fragment, U-1 (-474 to -7) using a transient transfection assay. The activity of the full-length U-1 DNA in HuH-7 hepatoma cells was 2- to 2.5-fold higher in the presence of thyroid hormone. This finding closely matched previous results using the in vitro nuclear run-on assay. Internal deletion of a motif that resembles a thyroid hormone response element from U-1 DNA not only abolished the induction by T3, but suppressed promoter activity by 3- to 4-fold in response to the hormone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of the thyroid hormone-responsive messenger RNA spot 11 as apolipoprotein-A1 messenger RNA and effects of the hormone on the promoter. 149 93

In mammals, the apolipoprotein (apo) A-I gene is expressed predominantly in liver and intestine, while in avian species it is expressed in all tissues. Although liver and intestine are the major sites of chicken apoA-I mRNA synthesis, there are appreciable amounts of apoA-I mRNA in kidney, ovary/testes, brain, lung, skeletal, and heart muscle. In this study, the nucleotide sequences of the chicken apoA-I gene and its 5' flanking region, as well as the sequences involved in the expression of this gene, have been determined. The gene spans 1.5 kilobases and contains 4 exons and 3 introns, closely resembling the mammalian apoA-I gene. To determine the sequences involved in the expression of the chicken apoA-I gene, plasmid constructs containing serial deletions of the 5' flanking region of the chicken apoA-I gene fused to the bacterial chloramphenicol acetyltransferase (CAT) gene were transfected in human hepatoma (HepG2), colon carcinoma (Caco2), epithelial (Hela), mouse embryonal fibroblast (NIH3T3) cells, and quail myoblasts (QMLA29). The shortest deletion construct, containing 60 bp of the 5' upstream region, was sufficient for maximal transcriptional activity in all cell lines tested. This region contains a short sequence (nucleotides -60 to -54) that is highly conserved in birds and mammals, and an Sp1 binding site. Although the sequence between nucleotides -232 and -101 of the 5' region of the chicken apoA-I gene is partially homologous to the hepatic cell-specific enhancer of the mammalian apoA-I gene (located between nucleotides -222 and -110 upstream of the human apoA-I gene transcription start site), this chicken sequence is transcriptionally inactive in HepG2 cells. These results suggest that differences in the cis-acting regulatory elements of the apoA-I gene play a fundamental role in determining the differences in the tissue-specific expression of this gene in avian and mammalian species.
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PMID:Evolutionary distinct mechanisms regulate apolipoprotein A-I gene expression: differences between avian and mammalian apoA-I gene transcription control regions. 151 10

Efflux of [14C]cholesterol from various cells was monitored in the presence of discoidal complexes of egg phosphatidylcholine and purified apolipoproteins, containing either apoAI, AII, or Cs. Particles containing apoAI were more efficient acceptors than those containing apoAII or Cs when the donor cells were J774 macrophages. No differences were observed when the same acceptor preparations were exposed to Fu5AH rat hepatoma or rabbit aortic smooth muscle cells. The differential efficiency of apolipoproteins in stimulating cholesterol removal from J774 cells was maintained in a plasma membrane-enriched fraction isolated from the same cells. Nonlinear regression analysis of kinetic data obtained from J774 cells exposed to apoAI complexes indicated that cholesterol efflux was best fitted to a curve describing the release from two kinetic compartments. Approximately 10% of cholesterol was transferred from a rapidly exchangeable pool with a t1/2 ranging between 1.5 and 3 h, and the remaining fraction was released from a slower pool with a t1/2 of about 20 h. Modulation of cholesterol efflux from J774 cells by either varying the concentration or the apolipoprotein composition of the acceptors influenced the size of the pools and the t1/2 of the slow pool. Kinetics of cholesterol efflux from membranes isolated from J774 cells also best fit a two-compartment model and modification of the apolipoprotein composition of the acceptor induced a pattern of changes in pool size and half-time similar to that described for whole cells. In the three cell lines studied, we consistently resolved a slow pool with a half-time ranging between 15 and 20 h. In smooth muscle cells only the slow pool was evident, whereas in Fu5AH a very large fast pool was also resolved. In contrast to J774 cells, apolipoprotein composition of the acceptor did not influence the pools in these two cell lines. These results led us to propose a new model regarding the influence of multiple kinetic pools of cholesterol on the regulation of cholesterol desorption from the cell membrane.
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PMID:Cellular cholesterol efflux. Role of cell membrane kinetic pools and interaction with apolipoproteins AI, AII, and Cs. 153 40

The synthesis and secretion of apolipoprotein (apo) E, a major protein component of very low density lipoproteins, were examined in the human hepatoma cell line HepG2 under metabolic conditions known to stimulate lipogenesis and the production of apoB-containing lipoproteins. When HepG2 cells were incubated in the presence of fetal bovine serum (5 or 10%) or canine chylomicron remnants (5 or 10 micrograms of protein), the secretion of triglycerides and cholesteryl esters of lipoproteins of d less than 1.063 g/ml increased, as determined by the incorporation of [14C]acetate. Determination of the distribution of apoE among media lipoproteins by agarose column chromatography showed that the majority of secreted apoE was associated with large lipoproteins when cells were incubated with fetal bovine serum. However, immunoblot analysis of total media apoE revealed that incubating cells with or without the lipogenic factors had no effect on the amount of apoE secreted. Pulse-chase and continuous labeling experiments demonstrated that the synthesis and secretion of apoE did not vary under the different metabolic conditions, even though there was a 5-fold increase in apoB secretion in response to increased lipogenesis. Neither apoE nor apoB mRNA levels responded to the lipogenic stimuli. We conclude that the synthesis and secretion of apoE are independent of the production of apoB-containing lipoproteins in HepG2 cells.
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PMID:Synthesis and secretion of apolipoprotein E occur independently of synthesis and secretion of apolipoprotein B-containing lipoproteins in HepG2 cells. 155 3

The estrogen-responsive Leghorn strain M chicken hepatoma (LMH) cell line provides a model system for studying the estrogen-dependent, liver-specific expression of avian genes. Serum-free culture conditions have been established that allow expression of apolipoprotein B, very low density apolipoprotein II (apoVLDLII), serum albumin, and transferrin at levels detectable by Northern blot analysis. Regulation of apoVLDLII mRNA by estrogen occurred in an appropriate time- and dose-dependent manner in serum-free cultures of the LMH cells. The expression of apoVLDLII mRNA in serum-free culture was at least 100-fold higher than that expressed in cultures containing 10% serum. The level of estrogen receptors in LMH cells cultured with 10% serum was approximately 2000 receptors per cell, and in serum-free culture approximately 1000 receptors per cell. When these cells were transfected with estrogen receptor DNA and cultured in serum-free medium, apoVLDLII mRNA was decreased relative to that expressed in cells transfected with a control plasmid. These results indicate that when the LMH cells are cultured without serum, estrogen receptors are not the limiting factor for the expression of the apoVLDLII gene.
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PMID:Estrogen-dependent expression of the chicken very low density apolipoprotein II gene in serum-free cultures of LMH cells. 163 38

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