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)

This paper describes some properties of glutamine oxidation and glutaminase isoform expression in cell lines derived from human colorectal adenomas and carcinomas. The slow-growing adenoma-derived cell line AA/C1, and the rapidly proliferating carcinoma cell line HT29, both required glutamine for growth. The rate of (14)CO(2) production from [U-(14)C]glutamine was faster in AA/C1 cells than in HT29 cells. Conversely HT29 cells showed faster rates of glucose oxidation and lactate production. The activity of glutaminase was 3 times higher in AA/C1 cell extracts than in extracts of HT29 cells. Glutaminase activity in the two cell lines had similar K(m) values for glutamine, but the activity in AA/C1 cells had a higher K(0.5) for activation by phosphate. Glutaminase activity in extracts of both cells was inhibited by glutamate. Western blotting showed the presence, in both cell lines, of isoform(s) of glutaminase with an molecular mass of 63 kDa, intermediate between that of kidney glutaminase and liver glutaminase. PCR-based analysis showed that an mRNA species identical to the kidney-type isoform glutaminase C was present in both cell types as was an additional mRNA species identical to the liver-type glutaminase isoform from human breast tumour cells. Northern blotting using isoform-specific cDNA probes demonstrated that mRNA for both glutaminase isoforms was expressed at significant levels in both cell types. Similar results to those in AA/C1 cells and HT29 cells were obtained in two further adenoma and carcinoma cell lines respectively. These results contrast with those reported previously in hepatocyte/hepatoma model systems with respect to fuel selection, glutaminase activity and isoform expression. They also constitute the first demonstration of simultaneous expression of two glutaminase isoforms in a single cell type.
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PMID:Glutaminase isoform expression in cell lines derived from human colorectal adenomas and carcinomas. 1240 49

The intervention of pyruvate in glucose metabolism was investigated during hypoxic stress in tumour cell cultures having respiratory capacities under normoxic conditions. Results obtained with nuclear magnetic resonance (NMR) spectroscopy showed that, under normoxic conditions, rat glioma C6 and human hepatoma Hep G2 cell cultures metabolised [(13)C(1)]glucose into lactate, alanine, glutamate and other less abundant metabolites, as already known from the literature. In the absence of pyruvate, during hypoxia or cyanide poisoning, both cell types dramatically decreased the label into glutamate and accumulated [(13)C(3)]glycerol-3-phosphate. The compound was further identified by 31P NMR spectroscopy. The accumulation of the label in glycerol-3-phosphate, however, did not occur when the cells were incubated in the presence of pyruvate. The fate of the latter, followed under normoxic conditions by incubating cells with [(13)C(3)]pyruvate and natural glucose, showed that the label was mainly found in alanine, lactate and glutamate. Anoxic conditions increased the label in lactate and reduced that of glutamate. The data show a metabolic effect of pyruvate during mitochondrial blockade due to severe lack of oxygen in tumour cell lines.
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PMID:Pyruvate reverses metabolic effects produced by hypoxia in glioma and hepatoma cell cultures. 1250 80

The six regulatory non-redundant ATPases in the base of the 19 S regulator of the 26 S proteasome belong to the AAA superfamily of ATPases. Yeast two-hybrid genetic screens, biochemical analyses and cell biological studies have identified and characterized new interactors of the human S6 (rpt3) and S8 (rpt6) ATPases of the 19 S regulator of the 26 S proteasome. The S6 ATPase interacts with gankyrin. This protein is found in purified human 26 S proteasomes and in a smaller complex(es) containing CDK4 and free S6 ATPase. Gankyrin overexpression causes the phosphorylation of the retinoblastoma protein (pRb) and the release of E2F transcription factor to trigger the expression of DNA synthesis genes. Gankyrin is oncogenic in nude mice and is overexpressed in hepatocellular carcinoma cells (HCCs). The S8 ATPase interacts with members of the large Homer-3 protein family. There are three Homer genes; the Homer 1 and 2 gene products control trafficking and calcium-store-related functions of metabotropic glutamate receptors (e.g. mGluR1alpha). Homer-3A11 by binding to the S8 ATPase brings mGluR1alpha to the 26 S proteasome for degradation. The degradation of mGluR1alpha is blocked by proteasomal inhibitors and by overexpression of the N-terminus of Homer which binds to the receptor. The S8 ATPase and mGluR1alpha are co-localized in Purkinje dendrites in rat cerebellum. The data are discussed in terms of the regulation of the cell cycle and glutaminergic receptor functions by the 26 S proteasome.
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PMID:Proteasomal interactors control activities as diverse as the cell cycle and glutaminergic neurotransmission. 1265 65

Whereas ch/ch wild-type mice and ch/14CoS heterozygotes are viable, 14CoS/14CoS mice homozygous for a 3800 kb deletion on chromosome 7 die during the first day postpartum. Death is caused by disruption of the fumarylacetoacetate hydrolase (Fah) gene; absence of FAH, final enzyme in the tyrosine catabolism pathway, leads to accumulation of reactive electrophilic intermediates. In this study, we kept 14CoS/14CoS mice alive for 60 d with oral 2-(2-nitro-4-trifluoromethyl-benzyol)-1,3-cyclohexanedione (NTBC), an inhibitor of p-hydroxyphenylpyruvate dioxygenase, second enzyme in the tyrosine catabolic pathway. The 70% of NTBC-treated 14CoS/14CoS mice that survived 60 d showed poor growth and developed corneal opacities, compared with ch/14CoS littermates; NTBC-rescued Fah(-/-) knockout mice did not show growth retardation or ocular toxicity. NTBC-rescued 14CoS/14CoS mice also exhibited a striking oxidative stress response in liver and kidney, as measured by lower GSH levels and mRNA induction of four genes: glutamate cysteine ligase catalytic (Gclc) and modifier (Gclm) subunits, NAD(P)H:quinone oxidoreductase (Nqo1), and heme oxygenase-1 (Hmox1). Withdrawal of NTBC for 24-48 h from rescued adult 14CoS/14CoS mice resulted in severe apoptosis of the liver, detected histologically and by cytochrome c release from the mitochondria, increased caspase 3-like activity, and further decreases in GSH content. In kidney, proximal tubular epithelial cells were abnormal. Human hereditary tyrosinemia type I (HT1), caused by mutations in the FAH gene, is an autosomal recessive disorder in which the patient usually dies of liver fibrosis and cirrhosis during early childhood; NTBC treatment is known to prolong HT1 children's lives-although liver fibrosis, cirrhosis, hepatocarcinoma, and corneal opacities sometimes occur. The mouse data in the present study are consistent with the possibility that endogenous oxidative stress-induced apoptosis may be the underlying cause of liver pathology seen in NTBC-treated HT1 patients.
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PMID:Pharmacological rescue of the 14CoS/14CoS mouse: hepatocyte apoptosis is likely caused by endogenous oxidative stress. 1289 38

This review describes some of the biochemical and toxicological properties of CYP2E1, especially as it relates to alcohol metabolism and toxicity and the establishment of human hepatoma HepG2 cell lines that overexpress human CYP2E1. Ethanol, polyunsaturated fatty acids, and iron were found to be cytotoxic in HepG2 cells that overexpress CYP2E1. GSH appears to be essential in protecting HepG2 cells against the CYP2E1-dependent cytotoxicity, and GSH levels were elevated owing to a twofold increase in activity and expression of glutamate cysteine ligase. We suggest that this up-regulation of GSH synthesis was an adaptive response to attenuate CYP2E1-dependent oxidative stress and toxicity. Induction of a state of oxidative stress appears to play a central role in the CYP2E1-dependent cytotoxicity. Mitochondrial membrane potential decreased in the CYP2E1-expressing HepG2 cells, and this decrease shared similar characteristics with the developing toxicity. Alcohol-dependent liver injury is likely to be a multifactorial process involving several mechanisms. We believe that the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, and GSH homeostasis contribute to the toxic actions of ethanol on the liver.
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PMID:Oxidative stress, toxicology, and pharmacology of CYP2E1. 1474 37

Hepatocellular carcinoma (HCC) is a common malignancy worldwide, the occurrence of which is unevenly distributed. Most hepatocellular carcinoma cases present late and have a poor prognosis; therefore, early diagnosis is essential to prolong survival. Differential diagnosis with magnetic resonance imaging (MRI) is difficult. We studied the feasibility of using magnetic resonance spectroscopy (MRS) at 7.0 T for the diagnosis and grading of liver tumors. An animal model of hepatocarcinogenesis was used, which allowed tumor progression from precancerous lesions to hepatocellular carcinomas. This study was focused primarily on the grading of the tumors and its correlation with the ratio between the MRS peaks arising from MRS-detected lipid hydrogens (0.9, 1.3 and 5.3 ppm) and compared to the gamma-methylene hydrogens of glutamate (Glu) and glutamine (Gln) which was used as an internal reference (2.4 ppm). The lipid methylene hydrogen (1.3 ppm) to (Glu + Gln) ratio was found to correlate with the formation of differentiated small foci and (precancerous) hepatic nodules, whereas the unsaturated olefinic lipid hydrogen (5.3 ppm) to (Glu + Gln) ratio was able to correlate with the formation of late stage tumors such as adenomas and hepatocellular carcinomas. The results of our study suggest that MRS-detected alterations in lipid metabolism can be correlated with the grading of liver tumor tissue at different stages during the carcinogenesis process.
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PMID:Hepatocarcinogenesis tumor grading correlated with in vivo image-guided 1H-NMR spectroscopy in a rat model. 1602 58

Schwann cells have been identified as targets for glucocorticoids. Besides genes implicated in the myelination process, the target genes of glucocorticoids have not been identified in these cells. For that purpose, we performed microarray analysis on MSC80 (mouse Schwann cells) treated with a synthetic glucocorticoid, dexamethasone. These cells express a functional glucocorticoid receptor (GR), but none of the other steroid receptors. This allowed us to identify genes specifically regulated by GR in the absence of the mineralocorticoid receptor. Among the 5000 genes analyzed, 12 were at least two-fold upregulated and 91 genes were at least two-fold down-regulated upon treatment with dexamethasone. Because of their potential role in Schwann cell homeostasis, we selected, for further analysis, the upregulated genes encoding glutamine synthetase (GS) and cytosolic aspartate aminotransferase (cAspAT). These genes play a crucial role in the glutamate cycle which was shown to be vital in neuron-astrocyte cross-talk in the central nervous system. Their activation was confirmed by semi-quantitative and real-time PCR. A detailed analysis of cAspAT promoter activity revealed that the mechanism of regulation by GR in Schwann cells differs from that in hepatoma cells, suggesting a cell-specific regulation. The transactivation potency of the two Glucocorticoid Responsive Units (GRU) present in the cAspAT promoter seems to be dependent on the levels of the GR in MSC80 cells. Furthermore, we show that an increase in GR levels under certain circumstances could considerably potentiate the effects of glucocorticoids on the cAspAT promoter via synergistic activation of both GRU, To the opposite, an enhancement in GR levels did not further potentiate Dex-activation of the GS promoter, showing a differential mechanism of action of GR in the context of both promoters.
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PMID:Identification by microarray analysis of aspartate aminotransferase and glutamine synthetase as glucocorticoid target genes in a mouse Schwann cell line. 1618 22

Citrin, encoded by SLC25A13, is a liver-type mitochondrial aspartate-glutamate carrier (AGC), of which deficiency, in autosomal recessive trait, causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). NICCD patients have jaundice, hypoproteinemia, hypoglycemia, galactosemia, growth retardation, fatty liver and multiple aminoacidemia including citrulline, methionine, threonine and tyrosine. Some of the neonates who have experienced NICCD suffer from severe CTLN2 more than 10 years or several decades later. In CTLN2, neuropsychotic symptoms such as disorientation, aberrant behavior, coma and death are observed. Laboratory findings reveal hyperammonemia, citrullinemia, fatty liver and liver-specific decrease in a urea cycle enzyme, argininosuccinate synthetase (ASS). In some cases, hyperlipidemia, pancreatitis and hepatoma are accompanied with CTLN2. Citrin as a liver-type AGC plays a role in supplying aspartate to the cytosol for urea, protein and nucleotide synthesis by exchanging mitochondrial aspartate for cytosolic glutamate and proton, and transporting cytosolic NADH reducing equivalent to mitochondria as a member of malate aspartate shuttle essential for aerobic glycolysis. AGC is also important for gluconeogenesis from lactate. Although it is difficult to explain pathogenesis of the symptoms such as cholestasis in NICCD and liver-specific decrease of ASS protein in CTLN2 from the functions of the AGC, some are understandable by the loss of citrin functions. Many CTLN2 patients have been treated with a low protein and high carbohydrate diet and glycerol at the hyperammonemic coma. We argue that those treatments may result in fatty liver, hyperlipidemia, hyperammonemia and even death due to loss of the citrin functions. Loss of citrin first cause deficiency of aspartate in the cytosol, which results in an increase in cytosolic NADH/NAD(+) ratio and then activation of fatty acid synthesis pathway to compensate the aberrant ratio. This follows inhibition of fatty acid oxidation. The peculiar fondness for food of CTLN2 patients who like protein and dislike carbohydrate and sweets may be related to their metabolic requirements.
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PMID:Metabolic derangements in deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier. 1619 99

Glutamine is the most abundant amino acid in the human body and can be synthesized by almost all tissues by the glutamine synthetase (GS)-catalyzed amidation of glutamate. Hepatocytes have access to extracellular glutamine by the concentrative uptake via members of the sodium-dependent neutral amino acid transport systems N and A. Hepatic glutamine metabolism in connection with urea synthesis is importantly involved in systemic ammonia detoxication and pH regulation due to the unique regulatory properties of the liver-type glutaminase, the acinar compartimentation of urea and glutamine synthesis, and a cycling of glutamine between periportal and perivenous hepatocytes. Upregulation of GS expression in hepatocellular carcinoma is related to growth advantage and an enhanced metastatic potential. Glutamine is a potent activator of signal transduction. Recent progress concerns the understanding of glutamine-induced hepatocyte swelling and the downstream activation of integrins, Src, and MAP-kinases in the regulation of autophagic proteolysis, canalicular bile acid excretion, glycogen and fatty acid synthesis, insulin signaling, and protection from apoptosis. Most recently the first primary GS defect leading to inherited glutamine deficiency with fatal outcome was described in human. This review summarizes recent progress in the understanding of glutamine metabolism and signal transduction, which provides further rationale for the use of glutamine as a therapeutic tool.
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PMID:Glutamine metabolism and signaling in the liver. 1712 5

High-resolution magic-angle spinning (MAS) 1H nuclear magnetic resonance spectroscopy has been employed to characterize the metabolite composition (i.e., metabonome) of the human hepatocellular carcinoma (HCC) tumor in combination with principal component analysis (PCA). The results showed that (a) the metabonomes of both low-grade HCC and high-grade HCC tumors differ markedly from that of the adjacent non-involved tissues; and (b) low-grade HCC tumors have clear differences in metabonome from that of the high-grade HCC tumors. Compared with the non-involved adjacent liver tissues, HCC tumors had elevated levels of lactate, glutamate, glutamine, glycine, leucine, alanine, choline metabolites, and phosphorylethanolamine (PE), but declined levels of triglycerides, glucose, and glycogen. The levels of lactate, amino acids including glutamate, glutamine, glycine, leucine and alanine, choline and phosphorylethanolamine (PE) were higher but the levels of PC, GPC, triglycerides, glucose, and glycogen were lower in high-grade HCC than in low-grade HCC tumors. Compared with non-cirrhotic, low-grade HCC tumors, the cirrhotic, low-grade HCC tumors showed statistically significant increases in lactate, phosphocholine (PC), and glycerophosphocholine (GPC). The necrosis in HCC tumors resulted in a drastic increase in the levels of observable triglycerides, signals of which dominated their 1H NMR spectra. These results indicated that HRMAS combined with PCA offers a useful tool for understanding the tumor biochemistry and classification of liver tumor tissues; such tool may also have some potential for liver tumor diagnosis and prognosis even when some other disease processes are present.
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PMID:Metabonomic studies of human hepatocellular carcinoma using high-resolution magic-angle spinning 1H NMR spectroscopy in conjunction with multivariate data analysis. 1756 25


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