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)

The mechanism of heme oxygenase-1 (ho-1) gene activation by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) was examined. 15d-PGJ(2) stimulated expression of HO-1 mRNA and protein and of a mouse ho-1 gene promoter/luciferase fusion construct (HO15luc) in a dose-dependent manner in mouse hepatoma (Hepa) cells. HO15luc expression was not effected by troglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand, but induction by 15d-PGJ(2) was abrogated by the antioxidant N-acetylcysteine. The primary 15d-PGJ(2) responsive sequences were localized to a 5' distal enhancer (E1) and identified as the stress-response element, previously shown to mediate ho-1 activation by several agents, including heme and heavy metals. Treatment of Hepa cells with 15d-PGJ(2) stimulated stress-response element-binding activity as judged by electrophoretic mobility shift assays. Antibody "supershift" experiments identified NF-E2 related factor 2 (Nrf2), but not Fos, Jun, or activating transcription factor/cyclic AMP response element binding protein transcription factors, within the 15d-PGJ(2)-induced complexes. Similarly, a dominant-negative mutant of Nrf2, but not of c-Jun or c-Fos, abrogated 15d-PGJ(2)-stimulated E1 transcription activity. Finally, prior induction of HO-1 in RAW264.7 mouse macrophages by 15d-PGJ(2) attenuated cell death caused by diesel exhaust particle extracts. These results demonstrate that induction of mouse HO-1 expression by 15d-PGJ(2) is independent of PPAR-gamma but dependent on oxidative stress, is regulated by the oxidative stress-activated transcription factor Nrf2, and provides cytoprotective activity.
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PMID:Activation of the mouse heme oxygenase-1 gene by 15-deoxy-Delta(12,14)-prostaglandin J(2) is mediated by the stress response elements and transcription factor Nrf2. 1200 76

C-reactive protein (CRP) is a major acute-phase protein in humans. Elevated plasma CRP levels are a risk factor for cardiovascular disease. CRP is predominantly expressed in hepatocytes and is induced by interleukin-1 (IL-1) and IL-6 under inflammatory situations, such as the acute phase. Fibrates are hypolipidemic drugs that act through the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Fibrates have been shown to reduce elevated CRP levels in humans, but the molecular mechanism is unknown. In this study, we demonstrate that different PPAR-alpha activators suppress IL-1-induced, but not IL-6-induced, expression of CRP in primary human hepatocytes and HuH7 hepatoma cells. Induction of CRP expression by IL-1 occurs at the transcriptional level. Site-directed mutagenesis experiments show that IL-1 induces CRP expression through 2 overlapping response elements, the binding sites for CCAAT-box/enhancer-binding protein-beta (C/EBP-beta) and p50-nuclear factor-kappaB (p50-NFkappaB). Cotransfection of C/EBP-beta and p50-NFkappaB enhances CRP promoter activity, and coimmunoprecipitation experiments indicate that the increase in CRP promoter activity by IL-1 is related to the generation and nuclear accumulation of C/EBP-beta-p50-NFkappaB complexes. Interestingly, PPAR-alpha activators reduce the formation of nuclear C/EBP-beta-p50-NFkappaB complexes, and thereby CRP promoter activity, by 2 mechanisms. First, PPAR-alpha increases IkappaB-alpha expression and thus prevents p50-NFkappaB translocation to the nucleus. Second, fibrates decrease hepatic C/EBP-beta and p50-NFkappaB protein levels in mice in a PPAR-alpha-dependent way. Our findings identify C/EBP-beta and p50-NFkappaB as novel targets for PPAR-alpha and provide a molecular explanation for the reduction of plasma CRP levels by fibrates.
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PMID:Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation. 1239 63

The peroxisome proliferator-activated receptor agonist troglitazone (TRO) was used for treatment of non-insulin-dependent diabetes until its removal from the market because of its severe hepatotoxicity. However, the mechanism for its hepatotoxicity is still poorly understood. In this study, we investigated whether TRO caused cell death by altering signaling pathways associated with cell damage and survival in human hepatoma cells. Our data reveal that TRO caused time- and concentration-dependent apoptosis of HepG2 and Chang liver human hepatoma cells, as evidenced by DNA fragmentation and staining with Hoechst 33342. In contrast, 50 or 100 microM rosiglitazone, a structural analog of TRO, did not cause apoptosis in these hepatoma cells. TRO activated both c-Jun N-terminal protein kinase (JNK) and p38 kinase about 5-fold between 0.5 and 8 h before they returned to control levels at 16 h in HepG2 cells. In contrast, TRO failed to activate the extracellular signal-regulated kinase. Furthermore, TRO increased the levels of proapoptotic proteins, Bad, Bax, release of cytochrome c, and cleavage of Bid in a time-dependent manner. The antiapoptotic Bcl-2 protein level decreased in hepatoma cells treated with TRO. Pretreatment of hepatoma cells with a selective JNK inhibitor, anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), significantly reduced the rate of TRO-induced cell death, whereas 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580), an inhibitor of p38 kinase, had little effect on apoptosis. Pretreatment with SP600125 also prevented JNK activation and c-Jun phosphorylation. In addition, rosiglitazone, which is not as toxic to hepatoma cells as TRO, did not stimulate JNK activity. Transfection of cDNA for the dominant-negative mutant JNK-KR (Lys-->Arg) or SEK1-KR (Lys-->Arg), an immediate upstream kinase of JNK, significantly reduced TRO-induced JNK activation and cell death rate. Furthermore, SP600125 pretreatment effectively prevented the TRO-mediated changes in Bad, Bax, Bid cleavage, and cytochrome c release. These data strongly suggest that hepatotoxic TRO causes apoptosis by activating the JNK-dependent cell death pathway accompanied by increased Bid cleavage and elevation of proapoptotic proteins.
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PMID:Critical role of c-Jun N-terminal protein kinase activation in troglitazone-induced apoptosis of human HepG2 hepatoma cells. 1252 12

Peroxisome proliferators (PPs) are an important class of chemicals that act as hepatic tumor promoters in laboratory rodents. The key target for PPs is the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPARalpha) and these chemicals cause cancer by altering the expression of a subset of genes involved in cell growth regulation. The purpose of the present study was to utilize high-density gene expression arrays to examine the genes regulated by the potent PP Wy14,643 (50 microM, 6 h) in both rat (FaO) and human (HepG2) hepatoma cells. Treatment of FaO cells, but not HepG2, revealed the expected fatty acid catabolism genes. However, a larger than expected number of protein kinases, phosphatases, and signaling molecules were also affected exclusively in the FaO cells, including MAPK-phosphatase 1 (MKP-1), Janus-activated kinases 1 and 2 (JAK1 and 2), and glycogen synthetase kinase alpha and beta (GSKalpha and beta). The mRNA accumulation of these genes as well as the protein level for GSK3alpha, JAK1, and JAK2 and MKP-1 activity was corroborated. Due to the importance of MKP-1 in cell signaling, this induction was examined further and was found to be controlled, at least in part, at the level of the gene's promoter. Interestingly, overexpression of MKP-1 in turn affected the constitutive activity of PPARalpha. Taken together, the gene expression arrays revealed an important subset of PP-regulated genes to be kinases and phosphatases. These enzymes not only would affect growth factor signaling and cell cycle control but also could represent feedback control mechanisms and modulate the activity of PPARalpha.
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PMID:Comprehensive analysis of gene expression in rat and human hepatoma cells exposed to the peroxisome proliferator WY14,643. 1272 18

The peroxisome proliferator-activated receptor-gamma (PPARgamma) high-affinity ligand, 15-deoxy-Delta-12,14-PGJ(2) (15d-PGJ(2)), is toxic to malignant cells through cell cycle arrest and apoptosis induction. In this study, we investigated the effects of 15d-PGJ(2) on apoptosis induction and expression of apoptosis-related proteins in hepatocellular carcinoma (HCC) cells. 15d-PGJ(2) induced apoptosis in SK-Hep1 and HepG2 cells at a 50 micro M concentration. Pretreatment with the pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (2-VAD-fmk), only partially blocked apoptosis induced by 40 micro M 15d-PGJ(2). This indicated that 15d-PGJ(2) induction of apoptosis was associated with a caspase-3-independent pathway. 15d-PGJ(2) also induced down-regulation of the X chromosome-linked inhibitor of apoptosis (XIAP), Bclx, and apoptotic protease-activating factor-1 in SK-Hep1 cells but not in HepG2 cells. However, 15d-PGJ(2) sensitized both HCC cell lines to TNF-related apoptosis-induced ligand-induced apoptosis. In SK-Hep1 cells, cell toxicity, nuclear factor-kappaB (NF-kappaB) suppression, and XIAP down-regulation were induced by 15d-PGJ(2) treatment under conditions in which PPARgamma was down-regulated. These results suggest that the effect of 15d-PGJ(2) was through a PPARgamma-independent mechanism. Although cell toxicity was induced when PPARgamma was down-regulated in HepG2 cells, NF-kappaB suppression and XIAP down-regulation were not induced. In conclusion, 15d-PGJ(2) induces apoptosis of HCC cell lines via caspase-dependent and -independent pathways. In SK-Hep1 cells, the ability of 15d-PGJ(2) to induce cell toxicity, NF-kappaB suppression, or XIAP down-regulation seemed to occur via a PPARgamma-independent mechanism, but in HepG2 cells, NF-kappaB suppression by 15d-PGJ(2) was dependent on PPARgamma.
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PMID:15-deoxy-delta-12-14-PGJ2 regulates apoptosis induction and nuclear factor-kappaB activation via a peroxisome proliferator-activated receptor-gamma-independent mechanism in hepatocellular carcinoma. 1456 54

Inflammatory processes, aside from cholesterol, play a central role in atherogenesis. Human C-reactive protein (huCRP) signals systemic inflammation and independently predicts future cardiovascular risk. Cholesterol-lowering statins reduce atherosclerosis and plasma huCRP levels. Evidence is sought for a direct anti-inflammatory statin effect in vivo, independent of effects on plasma cholesterol and atherogenesis. The effect of atorvastatin and simvastatin on huCRP expression was studied in nonatherosclerotic huCRP transgenic mice and compared with another class of hypolipidemic drugs, peroxisome proliferator-activated receptor-alpha (PPARalpha) activators, notably fenofibrate and Wy14643. Like statins, PPARalpha activators combine antiatherosclerotic properties with huCRP-lowering effects. Dietary treatment with statins or PPARalpha activators decreased basal and interleukin-1beta (IL-1beta)-induced plasma huCRP levels independently of cholesterol lowering. These direct anti-inflammatory in vivo effects occurred at the transcriptional level and could be confirmed in cultured human liver slices and in human hepatoma cells transiently transfected with a huCRP promoter-driven luciferase reporter. A molecular rationale for the suppression of IL-1-induced huCRP transcription is provided by showing that statins and PPARalpha activators up-regulate IkappaBalpha protein expression. This results in a reduced nuclear translocation of p50-nuclear factor kappa B (NFkappaB) and thereby decreased amounts of nuclear p50-NFkappaB approximately CCAAT/enhancer binding protein beta (C/EBPbeta) complexes, which determine the huCRP transcription rate. Our results provide conclusive evidence for a direct suppressive effect of statins and PPARalpha activators on huCRP expression independent of cholesterol lowering and atherogenesis.
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PMID:Evidence for anti-inflammatory activity of statins and PPARalpha activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro. 1497 45

Peroxisome proliferation is a well-defined pleiotropic effect that is mediated by the ligand inducible transcription factor peroxisome proliferator-activated receptor (PPAR) alpha. Because marked peroxisome proliferation occurs in rodents but not in humans, we aimed to elucidate the molecular and cellular determinants of this species-specificity in hepatocytes. Analysis of peroxisomal marker enzyme activities confirmed that peroxisome proliferators induced acyl-CoA oxidase (ACOX) and to a lesser extent catalase in rat hepatocytes, but not in human hepatoma HepG2 cells. Transient transfection assays revealed that ciprofibrate and Wy 14,643 induced rat but not human PPARalpha-mediated reporter gene activity in rat FAO and primary hepatocytes on rat but not on human PPARalpha response elements (PPREs). In contrast, in human HepG2 and primary human hepatocytes, peroxisome proliferators did not induce either human or rat PPARalpha activity regardless of rat or human PPRE sequences. In addition, no induction of ACOX gene expression was observed in human hepatocytes independent of the expression level of human PPARalpha. Remarkably, no distinct peroxisome proliferation related responses were observed in human hepatocytes when rat PPARalpha was transfected, although human hepatocytes were responsive to PPARalpha-mediated induction of carnitine palmitoyl transferase-1A and 3-hydroxy-3-methylglutaryl-CoA synthase. These results confirmed that PPARalpha and PPREs are important determinants for the species-specificity of peroxisome proliferation. Nevertheless, our results showed that human hepatocytes limit the extent of peroxisome proliferation regardless of PPARalpha expression.
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PMID:Characterization of the species-specificity of peroxisome proliferators in rat and human hepatocytes. 1497 57

The purpose of the present study was to examine the role of tangeretin, a polymethoxylated flavone from citrus fruits, on the regulation of apolipoprotein B (apoB) and lipid metabolism in the human hepatoma cell-line HepG2. The marked reduction in apoB secretion observed in cells incubated with 72.8 microM tangeretin was rapid, apoB-specific, and partly reversible. The reduction also was observed under lipid-rich conditions and found to be insensitive to proteasomal degradation of nascent apoB. We followed our study by examining lipid synthesis and mass. A 24-h exposure of cells to 72.8 microM tangeretin decreased intracellular synthesis of cholesteryl esters, free cholesterol, and TAG by 82, 45, and 64%, respectively; tangeretin also reduced the mass of cellular TAG by 37%. The tangeretin-induced suppression of TAG synthesis and mass were associated with decreased activities of DAG acyltransferase (up to -39.0 +/- 3.0% vs. control) and microsomal triglyceride transfer protein (up to -35.5 +/- 2.5% vs. control). Tangeretin was also found to activate the peroxisome proliferator-activated receptor, a transcription factor with a positive regulatory impact on FA oxidation and TAG availability (up to 36% increase vs. control). The data suggest that tangeretin modulates apoB-containing lipoprotein metabolism through multiple mechanisms.
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PMID:Modulation of HepG2 cell net apolipoprotein B secretion by the citrus polymethoxyflavone, tangeretin. 1513 41

The fasting-induced adipose factor (FIAF, ANGPTL4, PGAR, HFARP) was previously identified as a novel adipocytokine that was up-regulated by fasting, by peroxisome proliferator-activated receptor agonists, and by hypoxia. To further characterize FIAF, we studied regulation of FIAF mRNA and protein in liver and adipose cell lines as well as in human and mouse plasma. Expression of FIAF mRNA was up-regulated by peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARbeta/delta agonists in rat and human hepatoma cell lines and by PPARgamma and PPARbeta/delta agonists in mouse and human adipocytes. Transactivation, chromatin immunoprecipitation, and gel shift experiments identified a functional PPAR response element within intron 3 of the FIAF gene. At the protein level, in human and mouse blood plasma, FIAF was found to be present both as the native protein and in a truncated form. Differentiation of mouse 3T3-L1 adipocytes was associated with the production of truncated FIAF, whereas in human white adipose tissue and SGBS adipocytes, only native FIAF could be detected. Interestingly, truncated FIAF was produced by human liver. Treatment with fenofibrate, a potent PPARalpha agonist, markedly increased plasma levels of truncated FIAF, but not native FIAF, in humans. Levels of both truncated and native FIAF showed marked interindividual variation but were not associated with body mass index and were not influenced by prolonged semistarvation. Together, these data suggest that FIAF, similar to other adipocytokines such as adiponectin, may partially exert its function via a truncated form.
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PMID:The direct peroxisome proliferator-activated receptor target fasting-induced adipose factor (FIAF/PGAR/ANGPTL4) is present in blood plasma as a truncated protein that is increased by fenofibrate treatment. 1519 76

Amiodarone, an efficacious and widely used antiarrhythmic agent, has been reported to cause hepatotoxicity in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of amiodarone and examined for changes in hepatic histology and gene regulation. Amiodarone induced hepatomegaly, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum triglycerides and glucose. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for fatty acid oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPARalpha knockout [PPARalpha-/-] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPARalpha gene. Compared to wild-type mice, treatment of PPARalpha-/- mice with amiodarone resulted in an increased rate and extent of total body weight loss. The inability of amiodarone to directly activate either human or mouse PPARalpha transiently expressed in human HepG2 hepatoma cells indicates that the effects of amiodarone on the function of this receptor were indirect. Based upon these results, we conclude that amiodarone disrupts hepatic lipid homeostasis and that the increased expression of PPARalpha target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPARalpha protects against amiodarone-induced hepatotoxicity.
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PMID:Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation. 1526 79

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