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)

By the complementation of a yeast mutant defective in myo-inositol transport (Nikawa, J., Nagumo, T., and Yamashita, S. (1982) J. Bacteriol. 150, 441-446), we isolated two myo-inositol transporter genes, ITR1 and ITR2, from a yeast gene library. The ITR1 and ITR2 genes contained long open reading frames capable of encoding 584 and 612 amino acids with calculated relative molecular masses of 63,605 and 67,041, respectively. The sequence similarity between the ITR1 and ITR2 products was extremely high, suggesting that the two genes arose from a common ancestor. Both gene products show significant sequence homology with a superfamily of sugar transporters, including human HepG2 hepatoma/erythrocyte glucose transporter and Escherichia coli xylose transporter. Hydropathy analysis indicated that the ITR1 and ITR2 products are both hydrophobic and contain 12 putative membrane-spanning regions. Thus, yeast myo-inositol transporters could be classified into the sugar transporter superfamily. Gene disruption and tetrad analysis showed that yeast cells contain two separate myoinositol transporters. The ITR1 product was the major transporter and the ITR2 product the minor one in cells grown in minimum medium containing glucose. Northern blot analysis showed that ITR1 mRNA was much more abundant than ITR2 mRNA. The previously isolated myo-inositol transport mutant was determined to be defective in ITR1.
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PMID:Isolation and characterization of two distinct myo-inositol transporter genes of Saccharomyces cerevisiae. 204 Jun 26

The mechanism of glucose transported (GT) expression on the plasma membranes of hepatoma cells in rats induced by 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB) was studied. Cytochalasin B binding to plasma membrane fractions from control and 3'-MeDAB group in the absence of cold cytochalasin B showed 9,825 +/- 925 and 30,165 +/- 625 dpm/mg membrane protein. Scatchard plot analysis showed that the GTs present on the plasma membrane fractions in control and 3'-Me DAB groups were 5.0 and 16.0 pmol/mg membrane protein and their Kd values were 151 and 157 nM, respectively. These results suggest that the numbers of GTs in plasma membrane were increased in the 3'-Me DAB group compared to the control group. In contrast, the amounts of GTs in low density microsomal (LDM) fractions measured by a photoaffinity labeling technique using [3H]-cytochalasin B were 31,207 and 11,702 dpm/mg protein in the control and 3'-Me DAB group, respectively. These results suggest that GTs were translocated from LDM to plasma membranes during carcinogenesis. To confirm these results by an independent method 10% SDS-polyacrylamide gel electrophoresis was carried out. Gel slice No. 13 corresponding to MW of 45 kDa from plasma membrane fractions showed increased radioactivities in the 3'-Me DAB group compared to the control group. However, LDM fractions of the 3'-Me DAB group showed decreased radioactivities compared to the control group. Western blot analysis using anti-human RBC GT antibody present in the plasma membranes and LDM fractions from control and 3'-Me DAB groups did not show any significant difference, indicating low cross-reactivity between them. These results indicate that increased glucose transport seems to be more likely due to reciprocal redistribution of GTs between plasma membrane and LDM fractions.
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PMID:A study on the regulation of translocation of glucose transporters during hepatocarcinogenesis induced by 3'-Me DAB. 207 56

The mechanism of action of CS-045, a new orally active antidiabetic agent, was studied in vitro using cultured hepatoma cells (Hep G2) and muscle cells (BC3H-1). Treatment of both types of cultured cells with varying doses of CS-045 did not significantly alter insulin receptor binding. Basal and insulin-stimulated glucose transport in BC3H-1 cells was also unaltered by the drug. In contrast, CS-045 increased glycogen synthase I activity in both cell types. This effect was maximal after 24 hours and in Hep G2 cells was associated with a threefold increase in the apparent affinity of the enzyme for glucose-6-phosphate. Gluconeogenesis from lactate in Hep G2 cells was greatly reduced by CS-045 treatment. We conclude that CS-045 may act directly on muscle and liver cells to increase glucose utilization. It is also effective in reducing glucose production. These multiple effects may account in part for the ability of CS-045 to reduce blood sugar levels in vivo.
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PMID:In vitro studies on the action of CS-045, a new antidiabetic agent. 212 May 48

Complementary DNA of a rat brain glucose transporter gene was used to examine the expression of glucose-transporter messenger RNA in paired human hepatocellular carcinomas and adjacent nontumorous liver tissues, as well as in human hepatoma cell lines and human fetal liver samples. High expression of a major 2.8-kilobase glucose-transporter transcript was seen in all hepatoma cell lines and fetal liver samples examined, whereas a much lower level of expression was observed in liver tissues. When pairs of liver tissues were examined, elevation of glucose-transporter RNA levels was observed in most of the hepatocellular carcinoma tissues examined.
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PMID:Elevation of facilitated glucose-transporter messenger RNA in human hepatocellular carcinoma. 215 92

The prevalence of glucose intolerance has been studied by oral glucose tolerance test in 670 patients affected by chronic liver disease. The glycometabolic status was evaluated by criteria given by WHO in 1980. Sixty-nine subjects appeared to be affected by chronic persistent hepatitis and 140 by chronic active hepatitis. In these patients the prevalence of diabetic responses (DR) did not differ much from that of the general population in our geographic area. In contrast, a markedly higher frequency of DR appeared in a cirrhotic group of 401 patients compared to non-cirrhotic subjects. The cirrhotics, divided according to different disease stages, showed a higher DR frequency in decompensated patients than in well compensated patients, the prevalence reaching 63% in the former subgroup. The coincident presence of hepatocarcinoma - documented in 60 other cirrhotic patients - does not modify the prevalence of diabetes. Other risk factors for diabetes such as age, sex, and family history have been considered. Our results suggest that: (1) all these factors seem not to play a major role in the pathogenesis of alterations of glucose metabolism in patients suffering from chronic liver disease, and therefore (2) liver cirrhosis by itself might be a risk factor in the disturbance of glucose tolerance.
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PMID:Alterations of glucose metabolism in chronic liver disease. 215 13

Complementary DNA encoding a facilitative glucose transporter was isolated from a human hepatoma cell line (HepG2) cDNA library and subcloned into a metal-inducible mammalian expression vector, pLEN (California Biotechnology) containing human metallothionein gene II promoter sequences. Chinese hamster ovary (CHO) cells transfected with this transporter expression vector, pLENGT, exhibited a 2-17-fold increase in immunoreactive HepG2-type glucose transporter protein, as measured by protein immunoblotting with antipeptide antibodies directed against the HepG2-type glucose transporter C-terminal domain. Expression of the human glucose transporter was verified by protein immunoblotting with a mouse polyclonal antiserum that recognizes the human but not the rodent HepG2-type transporter. 2-Deoxy-D-glucose uptake was increased 2-7-fold in transfected cell lines. Polyclonal antisera directed against purified red blood cell glucose transporter were raised in several rabbits. Antiserum from one rabbit, delta, was found to bind to the surface of intact red cells but not to inside-out red cell ghosts. Using this delta-antiserum in intact cell-binding assays, 1.6-9-fold increases in cell surface expression of the human glucose transporter were measured in CHO-K1 cell lines transfected with the transporter expression vector. Measurements of total cellular glucose transporter immunoreactive protein using anti-HepG2 transporter C-terminal peptide serum, cell surface glucose transporter protein using delta-antiserum and 2-deoxyglucose uptake revealed proportional relationships among these parameters in transfected cell lines expressing different levels of transporter protein. Insulin increased 2-deoxyglucose uptake 40% in control CHO-K1 cells and in CHO-K1 cells expressing modest levels of the human glucose transporter protein. However, stimulation of sugar-uptake by insulin was only 10% in cells overexpressing human glucose transporter protein 9-fold, and no effect of insulin on sugar uptake was detected in several cell lines expressing very high levels (12-17-fold over controls) of human HepG2 glucose transporter protein. No insulin stimulation of anti-cell surface glucose transporter antibody binding was detected in any control or transfected CHO-K1 cell lines. These data indicate that a glucose transporter protein that is insensitive to insulin in HepG2 cells is regulated by insulin when expressed at low but not at high levels in insulin-response CHO-K1 cells. Additionally, the results suggest that insulin does not increase 2-deoxyglucose uptake by increasing the number of cell surface HepG2-type glucose transporters in CHO-K1 fibroblasts.
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PMID:Insulin action on activity and cell surface disposition of human HepG2 glucose transporters expressed in Chinese hamster ovary cells. 215 29

The redox tolerance test introduced in this article attempts to quantify the deterioration of hepatic mitochondrial energy metabolism by measuring the changes in arterial ketone body ratio in response to 75-g oral glucose loading, and is discussed in relation to its predictive value for assessing surgical risk in hepatectomy. The indicator, called redox tolerance index (RTI), represents a 100-fold cumulative enhancement of ketone body ratio relative to glucose level (100 x delta KBR/delta glucose). The redox tolerance index was significantly different between 31 liver cirrhotics and 10 normal volunteers (p less than 0.001). Subjects were divided into three classes (I: RTI greater than or equal to 1.0, II: 0.5 less than or equal to RTI less than 1.0, III: RTI less than 0.5). Postoperative mortality was significantly different among the three classes in 127 hepatic resections (chi 2 = 9.843, p less than 0.01). Of 97 hepatocellular carcinoma cases, major hepatic resections in class III showed significantly higher postoperative morbidity and mortality rates (p less than 0.05 and p less than 0.05, respectively). The present findings indicate that RTI based on redox theory is of potential value in predicting posthepatectomy outcome.
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PMID:Response of hepatic mitochondrial redox state to oral glucose load. Redox tolerance test as a new predictor of surgical risk in hepatectomy. 215 76

The mechanism of tumor-associated hypoglycemia was examined in 11 patients with hepatocellular carcinoma, 6 of whom presented with severe hypoglycemia and 5 in whom plasma glucose was persistently normal. Serum insulin levels in the hypoglycemic patients were low. Although total serum insulin-like growth factor II (IGF-II) levels in both groups of tumor patients were lower than normal, tumor tissue from hypoglycemic patients contained levels of IGF-II mRNA that were 10-20-fold higher than those present in normal liver. IGF-II immunoreactivity consisted in all cases of a mixture of both higher molecular weight forms and material having the character of IGF-II itself. The former comprised a greater proportion of total IGF-II, in patients with hypoglycemia. Studies to characterize the interactions of IGF-II with serum proteins showed that (a) the radiolabeled peptide bound to an approximately 40,000-D protein in sera from both hypoglycemic patients and normal subjects, (b) sera from hypoglycemic patients and normal subjects had similar capacity to bind the radiolabeled peptide, and (c) the apparent affinities of serum binding proteins for IGF-II were the same for both hypoglycemic patients and normal subjects. Whereas, acid extracted, tumor-derived IGF-II immunoreactive peptides with low or intermediate molecular weights bound to serum proteins in a manner indistinguishable from that of IGF-II itself, the highest molecular weight IGF-II immunoreactive peptide exhibited negligible ability to compete for radiolabeled ligand binding to serum proteins. The low affinity of serum binding proteins for this component suggests that high molecular weight IGF-II immunoreactivity might circulate free and be available for interaction with cell-surface receptors.
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PMID:Tumor hypoglycemia: relationship to high molecular weight insulin-like growth factor-II. 215 26

To examine the cellular mechanism responsible for impaired insulin action in ageing, we determined various in-vitro parameters involved in the pathogenesis of insulin resistance, i.e. basal and insulin-stimulated [14C]3-O-methylglucose transport (3OMG), 125I-labelled insulin binding, activation of insulin receptor kinase (IRKA) in intact cells, and number and subcellular distribution of glucose transporters in subcellular membrane fractions of adipocytes from 6- (FR-6) and 24- (FR-24) month-old Fischer rats. Ageing had no effect on basal 3OMG (12 +/- 4 vs 13 +/- 3 fmol/5 x 10(4) cells, means +/- S.E.M.); in contrast, in FR-24 rats insulin-stimulated 3OMG was markedly decreased by 43% when compared with that in FR-6 rats (158 +/- 14 vs 90 +/- 8 fmol/5 x 10(4) cells; P less than 0.01). Insulin binding to adipocytes from FR-6 rats was 2.40 +/- 0.38% compared with 2.28 +/- 0.47% in FR-24 (P not significant). Moreover, ageing had no significant effect on IRKA, as determined by insulin-stimulated (0, 1, 4 and 500 ng insulin/ml) 32P-incorporation into histone 2B. In subcellular membrane fractions, low density microsomes and plasma membranes, glucose transporter numbers were determined using [3H]cytochalasin B binding and immunodetection using an antiserum against the C-terminal peptide of the hepatoma-G2-glucose transporter. Cytochalasin B binding revealed that in the basal state the intracellular pool of glucose transporters was depleted in FR-24 by about 39% compared with low density microsomes from FR-6: (48.6 +/- 7.2 vs 29.8 +/- 5.5 pmol/mg membrane protein; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potential mechanism of insulin resistance in ageing: impaired insulin-stimulated glucose transport due to a depletion of the intracellular pool of glucose transporters in Fischer rat adipocytes. 216 28

The physiological importance of the glucose fatty acid cycle has been controversial. Many studies have failed to demonstrate an inhibitory effect of free fatty acids (FFA) on glucose utilization. Using both hepatoma cells (Hep G2) and human erythrocytes, which have poor oxidative capacity and metabolize glucose primarily anaerobically, we have demonstrated a unique stimulatory effect of FFA on glycolysis. Fructose 2,6-bisphosphate (F-2,6-P2) concentrations also increased significantly in Hep G2 cells incubated with palmitic acid. In contrast, F-2,6-P2 concentrations fell in primary cultured hepatocytes incubated with palmitic acid in association with increased oxidation of FFA and accumulation of beta-hydroxybutyrate. We propose that a stimulatory effect of FFA on glycolysis reported here for the first time may have been masked in previous studies performed in tissues in which the oxidation of FFA and the accumulation of intermediates such as citrate may have decreased F-2,6-P2 concentrations. We conclude that the spectrum of FFA effects in glycolysis probably depends on tissue oxidative capacity.
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PMID:A stimulatory effect of FFA on glycolysis unmasked in cells with impaired oxidative capacity. 216 2


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