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)

Elevation of plasma homocysteine levels has been recognized as an independent risk factor for the development of cardiovascular disease, a major complication of diabetes. Plasma homocysteine reflects a balance between its synthesis via S-adenosyl-L-methionine-dependent methylation reactions and its removal through the transmethylation and the transsulfuration pathways. Betaine-homocysteine methyltransferase (BHMT, EC 2.1.1.5) is one of the enzymes involved in the remethylation pathway. BHMT, a major zinc metalloenzyme in the liver, catalyzes the transfer of methyl groups from betaine to homocysteine to form dimethylglycine and methionine. We have previously shown that plasma homocysteine levels and the transsulfuration pathway are affected by diabetes. In the present study, we found increased BHMT activity and mRNA levels in livers from streptozotocin-diabetic rats. In the rat hepatoma cell line (H4IIE cells), glucocorticoids (triamcinolone) increased the level and rate of BHMT mRNA synthesis. In the same cell line, insulin decreased the abundance of BHMT mRNA and the rate of de novo mRNA transcription of the gene. Thus the decreased plasma homocysteine in various models of diabetes could be due to enhanced homocysteine removal brought about by a combination of increased transsulfuration of homocysteine to cysteine and increased remethylation of homocysteine to methionine by BHMT.
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PMID:Effects of diabetes and insulin on betaine-homocysteine S-methyltransferase expression in rat liver. 1635 68

We have previously reported a positive correlation between the expression of BHMT (betaine-homocysteine S-methyltransferase) and ApoB (apolipoprotein B) in rat hepatoma McA (McArdle RH-7777) cells [Sowden, Collins, Smith, Garrow, Sparks and Sparks (1999) Biochem. J. 341, 639-645]. To examine whether a similar relationship occurs in vivo, hepatic BHMT expression was induced by feeding rats a Met (L-methionine)-restricted betaine-containing diet, and parameters of ApoB metabolism were evaluated. There were no generalized metabolic abnormalities associated with Met restriction for 7 days, as evidenced by control levels of serum glucose, ketones, alanine aminotransferase and L-homocysteine levels. Betaine plus the Met restriction resulted in lower serum insulin and non-esterified fatty acid levels. Betaine plus Met restriction induced hepatic BHMT 4-fold and ApoB mRNA 3-fold compared with Met restriction alone. No changes in percentage of edited ApoB mRNA were observed on the test diets. An increase in liver ApoB mRNA correlated with an 82% and 46% increase in ApoB and triacylglycerol production respectively using in vivo Triton WR 1339. Increased secretion of VLDL (very-low-density lipoprotein) with Met restriction plus betaine was associated with a 45% reduction in liver triacylglycerol compared with control. Nuclear run-off assays established that transcription of both bhmt and apob genes was also increased in Met-restricted plus betaine diets. No change in ApoB mRNA stability was detected in BHMT-transfected McA cells. Hepatic ApoB and BHMT mRNA levels were also increased by 1.8- and 3-fold respectively by betaine supplementation of Met-replete diets. Since dietary betaine increased ApoB mRNA, VLDL ApoB and triacylglycerol production and decreased hepatic triacylglycerol, results suggest that induction of apob transcription may provide a potential mechanism for mobilizing hepatic triacylglycerol by increasing ApoB available for VLDL assembly and secretion.
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PMID:Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine-homocysteine S-methyltransferase. 1639 37

Cadmium is a toxic metal and no effective antidote exists at present. The aim of this study was to examine whether sulphur amino acids, involved in glutathione synthesis, can modulate cadmium toxicity in vitro. Two hepatoma cell lines (HepG2 and HTC cells) were exposed to cadmium chloride (0-100 microM) for 8h in control media or in media containing 1mM of homocysteine, cysteine or cystathionine. Cell viability was then assessed with the neutral red assay. In order to assess the mechanism by which homocysteine and cysteine modulate cadmium toxicity their ability to scavenge reactive oxygen species was determined as well as the potential to increase intracellular glutathione levels. The ability of the sulphur amino acids to prevent cadmium uptake by HTC and HepG2 cells was also assessed. The results indicate that homocysteine and cysteine protect efficiently both cell lines from cadmium chloride toxicity whereas cystathionine protects efficiently HTC cells but not HepG2 cells. This effect was shown to be dependent on the dose of each amino acid and increased protection from cadmium was observed with increasing concentrations of homocysteine and cysteine. Both amino acids prevented the formation of reactive oxygen species only when they were administered together with cadmium chloride. In addition homocysteine and cysteine did not increase intracellular glutathione levels. The results indicate that the mechanism by which sulphur amino acids protect from cadmium toxicity in vitro is due to the reduced uptake of the metal by the cells possibly by direct binding to the -SH group of the amino acids.
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PMID:Modulation of cadmium chloride toxicity by sulphur amino acids in hepatoma cells. 1644 73

Coffee is a complex mixture of chemicals that provides significant amounts of chlorogenic acid and caffeine. Unfiltered coffee is a significant source of cafestol and kahweol, which are diterpenes that have been implicated in the cholesterol-raising effects of coffee. The results of epidemiological research suggest that coffee consumption may help prevent several chronic diseases, including type 2 diabetes mellitus, Parkinson's disease and liver disease (cirrhosis and hepatocellular carcinoma). Most prospective cohort studies have not found coffee consumption to be associated with significantly increased cardiovascular disease risk. However, coffee consumption is associated with increases in several cardiovascular disease risk factors, including blood pressure and plasma homocysteine. At present, there is little evidence that coffee consumption increases the risk of cancer. For adults consuming moderate amounts of coffee (3-4 cups/d providing 300-400 mg/d of caffeine), there is little evidence of health risks and some evidence of health benefits. However, some groups, including people with hypertension, children, adolescents, and the elderly, may be more vulnerable to the adverse effects of caffeine. In addition, currently available evidence suggests that it may be prudent for pregnant women to limit coffee consumption to 3 cups/d providing no more than 300 mg/d of caffeine to exclude any increased probability of spontaneous abortion or impaired fetal growth.
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PMID:Coffee and health: a review of recent human research. 1650 75

The transsulfuration pathway converts homocysteine to cysteine and represents the metabolic link between antioxidant and methylation metabolism. The first and committing step in this pathway is catalyzed by cystathionine beta-synthase (CBS), which is subject to complex regulation, including allosteric activation by the methyl donor, S-adenosylmethionine (AdoMet). In this study, we demonstrate that methionine restriction leads to a >10-fold decrease in CBS protein levels, and pulse proteolysis studies reveal that binding of AdoMet stabilizes the protein against degradation by approximately 12 kcal/mol. These observations predict that under pathological conditions where AdoMet levels are diminished, CBS, and therefore glutathione levels, will be reduced. Indeed, we demonstrate this to be the case in a mouse model for spontaneous steatohepatitis in which the gene for the MAT1A isoenzyme encoding AdoMet synthetase has been disrupted, and in human hepatocellular carcinoma, where MAT1A is silenced. Furthermore, diminished CBS levels are associated with reduced cell viability in hepatoma cells challenged with tert-butyl hydroperoxide. This study uncovers a mechanism by which CBS is allosterically activated by AdoMet under normal conditions but is destabilized under pathological conditions, for redirecting the metabolic flux toward methionine conservation. A mechanistic basis for the coordinate changes in redox and methylation metabolism that are a hallmark of several complex diseases is explained by these observations.
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PMID:S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity. 1661 71

Cellular methylation imbalance is associated with tumor progression, hepatic cancer, and cardiovascular disease. S-Adenosylhomocysteine (SAH) is an inhibitor of cellular methyltransferases, and increasing evidence suggests that SAH rather than homocysteine (Hcy) plays a crucial role in mediating these disorders related to methylation imbalance. The anti-metastatic gene nm23-H1 was recently identified in murine and human cancer lines, and the expressions of nm23-H1 mRNA and protein have been shown to be useful tumor invasion markers. We investigated the relationships of tumor cell invasion activities with the intracellular levels of SAH and Hcy and the level of DNA methylation (measured as the cellular content of 5-methyldeoxycytidine, 5-mdc) in four hepatocarcinoma cell lines (Sk-Hep1, J5, Hep-G2, Hep-3B) and one normal liver cell line (Chang's liver cells) with different invasion activities (Sk-Hep1 > J5 > Hep-G2 = Hep-3B > Chang's liver cells). We found that the intracellular level of SAH was the highest in SK-Hep1 cells and was correlated with the invasion activities (r = 0.75, P = 0.008), whereas the level of intracellular Hcy was the highest in Chang's liver cells and was not significantly correlated with the invasion activities of these cell lines (r = 0.24, P = 0.38). The levels of 5-mdc increased with decreasing invasion activities of these cell lines (r = 0.82, P = 0.002), that is, the order of DNA hypomethylation in these cell lines was Sk-Hep1 > J5 > Hep-G2 = Hep-3B > Chang's liver cells, because the lower levels of 5-mdc% represent the higher DNA hypomethylation. Thus, our results demonstrate that SAH rather than Hcy is associated with invasion activities of hepatoma cells, and they suggest that SAH may play an important role in the invasion activities through DNA hypomethylation.
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PMID:Intracellular levels of S-adenosylhomocysteine but not homocysteine are highly correlated to the expression of nm23-H1 and the level of 5-methyldeoxycytidine in human hepatoma cells with different invasion activities. 1704 78

Cell hydration changes play a key role in the regulation of cell function and critically affect insulin sensitivity of carbohydrate- and protein metabolism. Here, the modulation of gene expression profiles by hyperosmolarity and insulin was examined in H4IIE rat hepatoma cells by cDNA/oligonucleotiode array-, Northern- and Western blot analysis. Osmosensitive expression of the insulin-like growth factor binding protein Igfbp1, the multidrug resistance protein Mrp5 (Abcc5a) and cyclin D1 (Ccnd1) was established at the mRNA and protein level. Despite a hyperosmotic increase of cyclin D1 mRNA induction by insulin, the cyclin D1 protein expression was decreased by hyperosmolarity, suggesting a hyperosmotic interference with cyclin D1 mRNA translation. Hyperosmolarity at the mRNA level blunted the insulin response of betaine homocysteine-S-methyl transferase, the multidrug resistance proteins Mdr1a (Abcb1a) and 2 (Abcb4), the Igfbp 2 and 5, cyclin G1, dual specificity phosphatase Dusp1, signal transducers and activators of transcription Stat3 and 5, catalase and the bile salt export pump Bsep (Abcb11), whereas the insulin response was increased for Mrp5, cyclin D1 and the phosphoenolpyruvate carboxykinase. Insulin effects on the mRNA expression of the eukaryotic initiation factor 4E binding protein 4e-bp1, tubulin, gene 33, growth hormone receptor, keratin18, ornithine decarboxylase and heme oxygenase 1 were largely insensitive to hyperosmolarity. The data indicate that hyperosmolarity differentially modulates insulin sensitivity at the level of gene expression.
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PMID:Modulation of gene expression profiles by hyperosmolarity and insulin. 1776 65

Although metabolome research is a rapidly expanding field in the postgenomic era, no single method exists for complete analysis of all the constituents of a metabolome. In this study, we developed a metabolome analysis method using a combination of capillary electrochromatography and electrospray ionization-mass spectrometry. The capillary electrochromatography column was prepared by surface modification of silica compounds (tetraethoxysilane and octyltriethoxysilane) in a fused-silica capillary column. The method was used to separate more than 100 charged and neutral compounds simultaneously. When 1 mM formic acid was used as the eluent, the cationic compounds were eluted rapidly, and then neutral and anionic compounds were eluted (in that order). The developed system was used to analyze the metabolome of a human hepatocellular carcinoma cell line (HepG2). Thirty-three peaks were detected, and eighteen compounds were identified, including marker compounds of hepatocellular cell activity, such as creatinine and homocysteine. Thus, the system was useful not only for metabolome analysis but also for diagnostic measurements of cell function.
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PMID:A capillary electrochromatography-electron spray ionization-mass spectrometry method for simultaneous analysis of charged and neutral constituents of a hepatocarcinoma cell metabolome. 1961 81

We previously reported that all-trans-retinoic acid (ATRA) induced apoptosis in N-acetylglucosaminyltransferase V (GnT-V) repressed human hepatocarcinoma 7721 (GnT-V-AS/7721) cells via endoplasmic reticulum (ER) stress. In addition to confirming these findings, we further found that ATRA repressed the expression of betaine-homocysteine methyltransferase (BHMT) and cystathionine-beta-synthase (CBS), which are key enzymes that are involved in homocysteine metabolism, increased the level of intracellular homocysteine, and decreased the glutathione (GSH) level in GnT-V-AS/7721 cells. To investigate the effect of ATRA on homocysteine metabolism, cells were challenged with exogenous homocysteine. In GnT-V-AS/7721 cells with ATRA treatment, a significant elevation of intracellular homocysteine levels suggests that ATRA perturbs homocysteine metabolism in GnT-V-AS/7721 cells and, therefore, sensitizes the cells to homocysteine-induced ER stress. An obvious increase in the levels of GRP78/Bip protein and spliced XBP1 mRNA were observed. Furthermore, we observed that ATRA blunted the homocysteine-induced increase of GSH only in GnT-V-AS/7721 cells. These results demonstrate that ATRA intensifies ER stress and induces apoptosis in GnT-V-AS/7721 cells by disturbing homocysteine metabolism through the down-regulation of CBS and BHMT, depleting the cellular GSH and, in turn, altering the cellular redox status. In addition, we showed that ATRA did not trigger ER stress, induce apoptosis, or affect homocysteine metabolism in L02 cells, which is a cell type that is derived from normal liver tissue. These results provide support for the hypothesis that ATRA is an anticancer agent.
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PMID:All-trans-retinoic acid intensifies endoplasmic reticulum stress in N-acetylglucosaminyltransferase V repressed human hepatocarcinoma cells by perturbing homocysteine metabolism. 1996 May 9

Glycine N-methyltransferase (GNMT) is a major hepatic enzyme that converts S-adenosylmethionine to S-adenosylhomocysteine while generating sarcosine from glycine, hence it can regulate mediating methyl group availability in mammalian cells. GNMT is also a major hepatic folate binding protein that binds to, and, subsequently, may be inhibited by 5-methyltetrafolate. GNMT is commonly diminished in human hepatoma; yet its role in cellular folate metabolism, in tumorigenesis and antifolate therapies, is not understood completely. In the present study, we investigated the impacts of GNMT expression on cell growth, folate status, methylfolate-dependent reactions and antifolate cytotoxicity. GNMT-diminished hepatoma cell lines transfected with GNMT were cultured under folate abundance or restriction. Folate-dependent homocysteine remethylation fluxes were investigated using stable isotopic tracers and gas chromatography/mass spectrometry. Folate status was compared between wild-type (WT), GNMT transgenic (GNMT(tg)) and GNMT knockout (GNMT(ko)) mice. In the cell model, GNMT expression increased folate concentration, induced folate-dependent homocysteine remethylation, and reduced antifolate methotrexate cytotoxicity. In the mouse models, GNMT(tg) had increased hepatic folate significantly, whereas GNMT(ko) had reduced folate. Liver folate levels correlated well with GNMT expressions (r = 0.53, P = 0.002); and methionine synthase expression was reduced significantly in GNMT(ko), demonstrating impaired methylfolate-dependent metabolism by GNMT deletion. In conclusion, we demonstrated novel findings that restoring GNMT assists methylfolate-dependent reactions and ameliorates the consequences of folate depletion. GNMT expression in vivo improves folate retention and bioavailability in the liver. Studies on how GNMT expression impacts the distribution of different folate cofactors and the regulation of specific folate dependent reactions are underway.
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PMID:GNMT expression increases hepatic folate contents and folate-dependent methionine synthase-mediated homocysteine remethylation. 2121 71

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