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 rat hepatoma-human fibroblast hybrid cell line WIF-B9 stably exhibits the structural and functional characteristics of normal differentiated hepatocytes. The abilities of these cells to synthesize bile acids and amidate them with glycine and taurine were investigated. The release of bile acids into the culture media over 72 h was assessed by gas chromatography-mass spectrometry. WIF-B9 cells were able to synthesize bile acids (1.10+/-0.17 nmol/mg protein) but less efficiently than rat hepatocytes in primary culture (2.19+/-0.19 nmol/mg protein; P<0.01). The patterns of major bile acid species produced by both types of cells were also different. Cholic acid (CA; 72%) and beta-muricholic acid (19%) were the major bile acids produced by rat hepatocytes, while chenodeoxycholic acid (CDCA) accounted for only 4.5% of total bile acids. In contrast, muricholic acids were absent, while CA (62%) and CDCA (34%) were the most abundant bile acids synthesized by WIF-B9 cells. Using reverse transcription-polymerase chain reaction and gene- and species-specific primers for key enzymes involved in bile acid synthesis, the expression of human, but not rat, orthologues of CYP7A1, CYP27, CYP8B and CYP7B1 was found in WIF-B9 cells. Induction of cell stress by serum deprivation did not change the amount of total bile acids synthesized by these cells, but an inversion of the CA-to-CDCA ratio from 1.8 to 0.3 together with a marked increase in the proportion of intermediate metabolites related to the acidic pathway was found. Using 500 microM radiolabeled CA and 2 mM of taurine or glycine, the ability to amidate CA over 48 h was determined by high performance liquid chromatography. Rat hepatocytes conjugated more than 90% CA with either amino acid, whereas this ability was very poor (< 2%) in WIF-B9 cells. Regarding the expression of enzymes and the products of bile acid synthesis, it may be concluded that the human phenotype predominates over that of the rat in WIF-B9 cells. Moreover, these cells are almost completely unable to further conjugate primary bile acids, which facilitates the manipulation of these steroids in analytical procedures. These characteristics make WIF-B9 cells a suitable in vitro model to carry out studies on bile acid synthesis by 'human-like' metabolic pathways.
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PMID:Predominance of human versus rat phenotype in the metabolic pathways for bile acid synthesis by hybrid WIF-B9 cells. 1175 Aug 86

We examined the molecular basis by which T3 regulates the human cholesterol 7alpha-hydroxylase gene (CYP7A1) promoter. L-T3 decreased chloramphenicol acetyltransferase activity in hepatoma cells cotransfected with a plasmid encoding the T3 receptor (TR) alpha [NR1a1] and a chimeric gene containing nucleotides -372 to +61 of the human CYP7A1 gene fused to the chloramphenicol acetyltransferase structural gene. Deoxyribonuclease I footprinting revealed that recombinant TRalpha protected two regions in this segment of the human CYP7A1 gene promoter. In EMSAs, TRalpha bound to both regions. The binding was competed by oligonucleotides bearing an idealized TRalpha binding motif and abolished by mutation of these elements. In assays of promoter function, mutation of only one of the TRalpha binding sites blocked repression by T3. The results indicate that T3-dependent repression of human CYP7A1 gene expression is mediated via a novel site in the human CYP7A1 gene promoter.
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PMID:A distinct thyroid hormone response element mediates repression of the human cholesterol 7alpha-hydroxylase (CYP7A1) gene promoter. 1177 35

Dietary cholesterol has been shown to have a stimulatory effect on the murine cholesterol 7alpha-hydroxylase gene (Cyp7a1), but its effect on human cholesterol 7alpha-hydroxylase gene (CYP7A1) expression in vivo is not known. A transgenic mouse strain harboring the human CYP7A1 gene and homozygous for the disrupted murine Cyp7a1 gene was created. Cholesterol feeding increased the expression of the endogenous modified Cyp7a1 allele but failed to stimulate the human CYP7A1 transgene. In transfected hepatoma cells, 25-hydroxycholesterol increased murine Cyp7a1 gene promoter activity, whereas the human CYP7A1 gene promoter was unresponsive. Electrophoretic mobility shift assays demonstrated the interaction of the liver X receptor alpha (LXRalpha): retinoid X receptor (RXR) heterodimer, a transcription factor complex that is activated by oxysterols, with the murine Cyp7a1 gene promoter, whereas no binding to the human CYP7A1 gene promoter was detected. The results demonstrate that the human CYP7A1 gene is not stimulated by dietary cholesterol in the intact animal, and this is attributable to the inability of the CYP7A1 gene promoter to interact with LXRalpha:RXR.
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PMID:Dietary cholesterol fails to stimulate the human cholesterol 7alpha-hydroxylase gene (CYP7A1) in transgenic mice. 1196 56

The acute phase response is associated with changes in the hepatic expression of genes involved in lipid metabolism. Nuclear hormone receptors that heterodimerize with retinoid X receptor (RXR), such as thyroid receptors, peroxisome proliferator-activated receptors, and liver X receptors, modulate lipid metabolism. We recently demonstrated that these nuclear hormone receptors are repressed during the acute phase response induced by lipopolysaccharide (LPS), consistent with the known decreases in genes that they regulate. In the present study, we show that LPS significantly decreases farnesoid X receptor (FXR) mRNA in mouse liver as early as 8 h after LPS administration, and this decrease was dose-dependent with the half-maximal effect observed at 0.5 microg/100 g of body weight. Gel-shift experiments demonstrated that DNA binding activity to an FXR response element (IR1) is significantly reduced by LPS treatment. Supershift experiments demonstrated that the shifted protein-DNA complex contains FXR and RXR. Furthermore, the expression of FXR target genes, SHP and apoCII, were significantly reduced by LPS (70 and 60%, respectively). Also, LPS decreases hepatic LRH expression in mouse, which may explain the reduced expression of CYP7A1 in the face of SHP repression. In Hep3B human hepatoma cells, both tumor necrosis factor (TNF) and interleukin-1 (IL-1) significantly decreased FXR mRNA, whereas IL-6 did not have any effect. TNF and IL-1 also decreased the DNA binding activity to an IR1 response element and the expression of SHP and apoCII. Importantly, TNF and IL-1 almost completely blocked the expression of luciferase activity linked to a FXR response element promoter construct transfected into Hep3B cells. Together with our earlier studies on the repression of RXRs, peroxisome proliferator-activated receptors, LXRs, thyroid receptors, constitutive androstane receptor, and pregnane X receptor, these results suggest that decreases in nuclear hormone receptors are major contributors to the decreased gene expression that occurs in the negative acute phase response.
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PMID:Repression of farnesoid X receptor during the acute phase response. 1251 62

L35 and FAO cells were derived as single cell isolates from H35 cells. Whereas L35 cells do not express microsomal triglyceride transfer protein (MTP), which regulates lipoprotein secretion, they express CYP7A1, which regulates bile acid synthesis from cholesterol. FAO cells display the opposite phenotype (i.e. expression of MTP but not CYP7A1). We examined the molecular basis of the transcriptional inactivation of the MTP gene in L35 cells. Nested deletion and mutagenesis studies show that a conserved DR1 element within the 135-bp proximal MTP promoter is responsible for differential expression by L35 and FAO cells. Yeast one-hybrid screening identified apolipoprotein A1 regulatory protein-1/chicken ovalbumin upstream promoter transcription factor II (ARP-1/COUP-TFII) and retinoid X receptor (RXRalpha) as the protein factors that can bind to the conserved DR1 element. Nuclear extracts from L35 cells contained 2-fold more ARP-1/COUP-TFII and 50% less RXRalpha than those from FAO cells. Immunologic studies show that in L35 cells, ARP-1/COUP-TFII is bound to the DR1 element, whereas in FAO cells, a complex containing RXRalpha is bound to the DR1 element. Co-transfection studies show that ARP-1/COUP-TFII repressed MTP promoter activity by approximately 70% in FAO hepatoma cells, whereas RXRalpha and its ligand 9-cis-retinoic acid increased MTP promoter activity by 6-fold in L35 cells. The combined data suggest that in the context of the MTP promoter, ARP-1/COUP-TFII (repressor) and a complex containing RXRalpha (inducer) compete for the DR1 element. Analysis of the CYP7A1 promoter revealed that it is approximately 5-fold more active in L35 cells than in FAO cells. Co-transfection of an ARP-1/COUP-TFII expression vector showed that it enhances CYP7A1 promoter activity by 6-fold in FAO cells. These combined findings indicate that ARP-1/COUP-TFII acts as both a transcriptional repressor (of MTP) and as a transcription activator (of CYP7A1). This dual function of ARP-1/COUP-TFII may play an important role in determining the metabolic phenotype of individual liver cells.
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PMID:ARP-1/COUP-TF II determines hepatoma phenotype by acting as both a transcriptional repressor of microsomal triglyceride transfer protein and an inducer of CYP7A1. 1277 84

Liver X receptors (LXR) alpha and beta play an important role in regulating the expression of genes involved in hepatic bile and fatty acid synthesis, glucose metabolism, as well as sterol efflux. Studies with human embryonic kidney 293 cells indicate that unsaturated fatty acids interfere with oxysterols binding to LXR and antagonize oxysterol-induced LXRalpha activity. In this report, we evaluated the effects of unsaturated fatty acids on LXR-regulated hepatic gene expression. The LXR agonist, T1317, induced mRNAs encoding sterol regulatory element-binding protein 1c (SREBP-1c) and two SREBP-1c-regulated lipogenic genes, e.g. fatty-acid synthase and the S14 protein in primary hepatocytes. Treatment of hepatocytes with eicosapentaenoic acid (20:5n-3) suppressed these mRNAs in the absence and presence of T1317. The cis-regulatory elements targeted by T1317 were not required for fatty-acid suppression of FAS or S14 promoter activity. In contrast to SREBP-1-regulated lipogenic genes, 20:5n-3 had no effect on the T1317 induction of ABCG5 or ABCG8 in the rat hepatoma cell line, FTO-2B. These two genes require LXR but not SREBP-1c for their expression. Feeding rats a diet supplemented with fish oil suppressed hepatic SREBP-1c-regulated genes and induced PPARalpha-regulated genes but had no effect on the LXR-regulated transcripts, CYP7A1, ABCG5, or ABCG8. Transfection studies, using either full-length hLXRalpha or a chimera containing only the LXRalpha ligand binding domain, indicate that a wide array of unsaturated fatty acids had little effect on LXRalpha activity in primary hepatocytes or FTO-2B. These studies suggest that LXRalpha is not a target for unsaturated fatty acid regulation in primary rat hepatocytes or in liver. Thus, oxysterol/LXR-mediated regulation of transcripts involved in bile acid synthesis or sterol efflux appear insensitive to dietary unsaturated fatty acids. The unsaturated fatty acid suppression of SREBP-1 and its targeted lipogenic genes is independent of LXRalpha
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PMID:The role of liver X receptor-alpha in the fatty acid regulation of hepatic gene expression. 1291 10

In previous work, we showed that the binding of the liver x receptor alpha:peroxisome proliferator-activated receptor alpha (LXRalpha:PPARalpha) heterodimer to the murine Cyp7a1 gene promoter antagonizes the stimulatory effect of their respective ligands. In this study, we determined if LXRalpha:PPARalpha can also regulate human CYP7A1 gene promoter activity. Co-expression of LXRalpha and PPARalpha in McArdle RH7777 hepatoma cells decreased the activity of the human CYP7A1 gene promoter in response to fibrates and 25-hydroxycholesterol. In vitro, the human CYP7A1 Site I bound LXRalpha:PPARalpha, although with substantially less affinity compared with the murine Cyp7a1 Site I. The binding of LXRalpha:PPARalpha to human CYP7A1 Site I was increased in the presence of either LXRalpha or PPARalpha ligands. In HepG2 hepatoblastoma cells, fibrates and 25-hydroxycholesterol inhibited the expression of the endogenous CYP7A1 gene as well as the human CYP7A1 gene promoter when co-transfected with plasmids encoding LXRalpha and PPARalpha. However, a derivative of the human CYP7A1 gene promoter that contains a mutant form of Site I that does not bind LXRalpha:PPARalpha was not inhibited by WY 14,643 or 25-hydroxycholesterol in both McArdle RH7777 and HepG2 cells. The ligand-dependent recruitment of LXRalpha:PPARalpha heterodimer onto the human CYP7A1 Site I can explain the inhibition of the human CYP7A1 gene promoter in response to fibrates and 25-hydroxycholesterol.
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PMID:The inhibition of the human cholesterol 7alpha-hydroxylase gene (CYP7A1) promoter by fibrates in cultured cells is mediated via the liver x receptor alpha and peroxisome proliferator-activated receptor alpha heterodimer. 1496 Jul 21

The gene encoding cholesterol 7alpha-hydroxylase (CYP7A1) is tightly regulated in order to control intrahepatic cholesterol and bile acid levels. Ligands of the xenobiotic-sensing pregnane X receptor inhibit CYP7A1 expression. To retrace the evolution of the molecular mechanisms underlying CYP7A1 inhibition, we used a chicken hepatoma cell system that retains the ability to be induced by phenobarbital and other drugs. Whereas bile acids regulate CYP7A1 via small heterodimer partner and liver receptor homolog-1, mRNA expression of these nuclear receptors is unchanged by xenobiotics. Instead, drugs repress chicken hepatic nuclear factor 4alpha (HNF4alpha) transcript levels concomitant with a reduction in CYP7A1 expression. Importantly, no reduction of HNF4alpha levels is found in mouse liver in vivo and in human primary hepatocyte cultures, respectively. Thus, besides the importance of HNF4alpha in CYP7A1 regulation in all species, birds and mammals use different signaling pathways to adjust CYP7A1 levels after exposure to xenobiotics.
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PMID:Species-specific mechanisms for cholesterol 7alpha-hydroxylase (CYP7A1) regulation by drugs and bile acids. 1562 11

The activity of cholesterol 7alpha-hydroxylase (gpCYP7A1), the rate limiting enzyme in bile acid synthesis, has been postulated to be regulated by phosphorylation/dephosphorylation. This study has found that several kinase activators rapidly reduce the amount of bile acid produced by the human hepatoma cell line, HepG2, and that gpCYP7A1 from HepG2 cell extracts eluted in the phosphoprotein fraction of FeIII columns. After incubating the HepG2 cells with radioactive orthophosphate, the band identified as gpCYP7Al on immunoblots was strongly labeled. Recombinant gpCYP7A was expressed as 6xHIS fusion polypeptides and subjected to kinase assays. The locations of phosphorylation were mapped further by screening synthetic peptides against AMP-activated protein kinase (AMPK), c-Jun N-terminal kinase, protein kinase A, and a panel of nine protein kinase C isoforms. AMPK, also known as 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase, phosphorylated cholesterol 7alpha-hydroxylase, suggesting a potential mechanism of coordination of cholesterol synthesis and degradation.
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PMID:Cholesterol 7alpha-hydroxylase is phosphorylated at multiple amino acids. 1575 49

Taurine has been reported to enhance cholesterol 7alpha-hydroxylase (CYP7A1) mRNA expression in animal models. However, no in vitro studies of this effect have been reported. The Hep G2 human hepatoma cell line has been recognized as a good model for studying the regulation of human CYP7A1. This work characterizes the effects of taurine on CYP7A1 mRNA levels of Hep G2 cells in a dose- and time-dependent manner. In the dose-dependent experiment, Hep G2 cells were treated with 0, 2, 10 or 20 mM taurine in the presence or absence of cholesterol 0.2 mM for 48 h. In the time-dependent experiment, Hep G2 cells were treated with 0 or 20 mM taurine for 4, 24 and 48 h with and without cholesterol 0.2 mM. Our data revealed that taurine showed time- and dose-response effects on CYP7A1 mRNA levels in Hep G2 cells. However, glycine - a structural analogue of taurine - did not have an effect on CYP7A1 gene expression. These results show that, in agreement to previous studies on animal models, taurine induces the mRNA levels of CYP7A1 in Hep G2 cells, which could enhance cholesterol conversion into bile acids. Also, Hep G2 cell line may be an appropriate model to study the effects of taurine on human cholesterol metabolism.
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PMID:Enhancing effect of taurine on CYP7A1 mRNA expression in Hep G2 cells. 1615 15

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