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)

The activity of ornithine decarboxylase (ODC) in H-35 hepatoma cells depleted of Ca2+ by washing with 2 mM EGTA increased 35-fold after incubating for 4 h in a simple salt-glucose solution containing 10 mM L-asparagine and only if Ca2+ was replenished. Actinomycin D (5 micrograms/ml) and cycloheximide (20 microM) reduced the stimulatory effect by 84 and 100% respectively. Increase of active enzyme protein was also demonstrated by a 3-fold increase in alpha-difluoromethylornithine binding. Asparagine prolonged the half-life of induced ODC by 20% whereas Ca2+ reduced it by 32%. The observed inductive effects are not accounted for entirely by a direct influence of Ca2+ and asparagine on the turnover of ODC protein. These factors are likely to be parts of a signalling pathway leading to amplification of cellular ODC.
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PMID:Relationship between Ca2+ and L-asparagine in the induction of ornithine decarboxylase in H-35 rat hepatoma cells. 144 90

Hexokinase plays an important role in normal glucose-utilizing tissues like brain and kidney, and an even more important role in highly malignant cancer cells where it is markedly overexpressed. In both cell types, normal and transformed, a significant portion of the total hexokinase activity is bound to particulate material that sediments upon differential centrifugation with the crude "mitochondrial" fraction. In the case of brain, particulate binding may constitute most of the total hexokinase activity of the cell, and in highly malignant tumor cells as much as 80 percent of the total. When a variety of techniques are rigorously applied to better define the particulate location of hexokinase within the crude "mitochondrial fraction," a striking difference is observed between the distribution of hexokinase in normal and transformed cells. Significantly, particulate hexokinase found in rat brain, kidney, or liver consistently distributes with nonmitochondrial membrane markers whereas the particulate hexokinase of highly glycolytic hepatoma cells distributes with outer mitochondrial membrane markers. These studies indicate that within normal tissues hexokinase binds preferentially to nonmitochondrial receptor sites but upon transformation of such cells to yield poorly differentiated, highly malignant tumors, the overexpressed enzyme binds preferentially to outer mitochondrial membrane receptors. These studies, taken together with the well-known observation that, once solubilized, the particulate hexokinase from a normal tissue can bind to isolated mitochondria, are consistent with the presence in normal tissues of at least two different types of particulate receptors for hexokinase with different subcellular locations. A model which explains this unique transformation-dependent shift in the intracellular location of hexokinase is proposed.
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PMID:Hexokinase receptors: preferential enzyme binding in normal cells to nonmitochondrial sites and in transformed cells to mitochondrial sites. 150 8

Twenty pancreata of non-diabetic patients and 17 pancreata of diabetic patients, including two patients with insulin-dependent diabetes mellitus, were immunohistochemically studied using antiserum against human islet amyloid polypeptide (IAPP). The islet beta cells in non-diabetic patients were immunoreactive for both IAPP and insulin. Amyloid deposition immunoreactive for IAPP was detected in six of 20 pancreata of non-diabetic patients. The plasma glucose level of three of these six patients was elevated to more than 200 mg/dl, and that of the other three ranged from 143 to 162 mg/dl; all six were receiving intravenous hyper-alimentation and had no history of diabetes prior to treatment. Amyloid deposition was present in all patients with non-insulin-dependent diabetes mellitus (NIDDM). The deposition was absent in the pancreata of two secondary diabetic patients, one of whom had received steroid hormone for bronchial asthma and the other of whom had liver cirrhosis with hepatocellular carcinoma; deposition was also absent in the pancreas of a patient with impaired glucose tolerance diagnosed on a 75-g oral glucose load. Heterogeneous expression of immunoreactivities of beta cells for insulin and for IAPP was present, suggesting independently regulated production and secretion of the peptides. Immunoreactivity of beta cells was more sensitively decreased for IAPP than for insulin in the islets of NIDDM patients. The decreased immunoreactivity for IAPP suggested an initial stage of disturbed beta-cell function, even if the immunoreactivity for insulin was apparently intact or the amyloid deposition in the islets was insignificant. The degree of amyloid deposition immunoreactivity for IAPP did not necessarily reflect the severity of diabetes mellitus. Amyloid deposits were seen at the narrow spaces beneath the insular capsule of connective tissues and the perivascular region or, in some cases, occupying the whole of the islet. The diabetogenic role of IAPP is unclear, but the deposition might be an accelerating factor which disturbs beta-cell function.
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PMID:Islet amyloid polypeptide (IAPP) and pancreatic islet amyloid deposition in diabetic and non-diabetic patients. 154 Dec 32

Glycogen phosphorylase isoenzymes were isolated from normal rat liver, rat brain, the glycogen-poor Morris hepatoma (MH) 3924A, and the glycogen-rich non-tumorigenic liver cell line C1I. Electrophoretic and immunological characterization of the enzymes showed that tumour and C1I cells expressed a phosphorylase isoform similar to the brain type; the liver type was not detectable. All enzymes were obtained as dimers; the Mr of the subunits was 96,000 (liver), 93,000 (brain and MH 3924A) and 92,000 (C1I). Isoelectric focusing revealed a main band of pI 6.34 for liver phosphorylase a, pI 5.67 for the enzymes from MH 3924A and brain, and pI 5.68 for C1I phosphorylase. Partial kinetic characterization of the AMP-independent forms of the isoenzymes yielded Km values for glucose 1-phosphate of 3.5 +/- 0.5 mM (liver), 3.9 mM (brain), 1.9 +/- 0.3 mM (MH 3924A) and 2.5 +/- 0.5 mM (C1I); Km values for glycogen were 0.4 mM (liver) and 0.3 mM (MH 3924A and C1I), calculated as glucose equivalents. The AMP-independent phosphorylase was inhibited by glucose 6-phosphate (Glc6P) with Ki values of 0.32 +/- 0.03 mM (C1I), 0.50 +/- 0.04 mM (MH 3924A) and approximately 5 mM (brain). The inhibition could be abolished by 1 mM-AMP, indicating that AMP and Glc6P may partially compete for the same site on the protein. Liver phosphorylase a was not inhibited by up to 25 mM-Glc6P. In contrast with liver and brain isoenzymes, phosphorylase from the cell lines was not affected by NaF and Na2SO4. The data show that both the hepatocellular carcinoma and the non-malignant immortalized liver cells express a phosphorylase isoform different from the liver type. Furthermore, there is some evidence that the enzyme from MH 3924A and C1I cells is distinct from brain phosphorylase a, in spite of electrophoretic and immunological resemblance, and that this isoenzyme is subject to altered metabolic regulation.
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PMID:Glycogen phosphorylase isoenzymes from hepatoma 3924A and from a non-tumorigenic liver cell line. Comparison with the liver and brain enzymes. 155 49

A constant supply of blood-borne glucose is vital to cerebral metabolism. Although transport of glucose into the nervous tissue, effectively separated from the blood by a functional barrier (the blood-brain barrier, BBB), is one of the essential properties of the cerebral endothelium, little is known about its metabolic regulation and developmental expression in the BBB. In this study we provide evidence by immunocytochemistry that the pattern of the brain endothelial glucose transporter in rat brains (BBB-GT), immunologically homologous with the human hepatoma (G2), human erythrocyte transporter (Glut 1), changes with BBB maturation. While the neuroepithelium at embryonic days 12 and 13 shows a high incidence of immuno-detectable BBB-GT, vascularisation of the cerebral anlage and subsequent development of vascular tightness, as evidenced by intravascularly applied horseradish peroxidase and fluorescinated dextrans, is accompanied by a significant reduction of BBB-GT expression in neuroepithelial cells and confinement of BBB-GT expression to the cerebral endothelium. Immunoblots and Northern blots of embryonic brain homogenates corroborate this change in BBB-GT expression in the brain anlage at the time of BBB maturation. However, low molecular weight glucose transporters, presumed to be of non-endothelial origin, are less dramatically reduced. The development of BBB tightness, therefore, seems to play a pivotal role in the pattern of BBB-GT expression during brain differentiation.
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PMID:Pattern of glucose transporter (Glut 1) expression in embryonic brains is related to maturation of blood-brain barrier tightness. 158 3

Hepatic glucose production is stimulated in vitro twice as effectively by pulsatile as by continuous glucagon, given equivalent time-averaged doses. Efficacy studies of pulsatile insulin have yielded conflicting results. In the rat hepatoma cell line H-4-II-E-C3, insulin rapidly (t1/2 15 min) inhibits transcription of the gene and lowers mRNA levels for the gluconeogenic enzyme. PEPCK via a receptor-mediated process. We attached H-4-II-E-C3 cells to Cytodex-3 microcarriers and used a perifusion column system to test whether pulsatile insulin is more or less effective than equivalent time-averaged doses of continuous insulin. PEPCK transcription was induced by inclusion of cAMP analogue 8-(4-chlorophenyl-thio)-cAMP (0.1 mM) and dexamethasone (0.5 microM) in the perifusion medium. Three columns were exposed either to continuous, pulsatile, or no insulin. After 3 h, total nucleic acid was extracted, and mRNA(PEPCK) was measured with a sensitive-solution hybridization assay. Continuous insulin inhibited PEPCK expression in a dose-dependent fashion with EC50 1 x 10(-11) M. Equivalent time-averaged amounts of insulin delivered as pulses achieved significant inhibition but less effectively than continuous insulin. The apparent EC50 for pulsatile insulin increased from 2 x 10(-11) M to 5 x 10(-11) M as the oscillatory period was raised from 5 to 20 min, respectively. These observations suggest that insulin-mediated inhibition of PEPCK gene transcription is diminished by a pulsatile mode of administration in marked contrast to the pulse enhancement demonstrated for glucagon-mediated hepatic glucose production.
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PMID:Insulin pulses less effective than continuous insulin in inhibiting PEPCK mRNA levels stimulated by cAMP and dexamethasone in perifused hepatoma cells. 165 Mar 13

Insulin stimulates glucose transport in adipocytes via the rapid redistribution of the GLUT1 and GLUT4 glucose transporters from intracellular membrane compartments to the cell surface. Insulin sensitivity is dependent on the proper intracellular trafficking of the glucose transporters in the basal state. The bulk of insulin-sensitive transport in adipocytes appears to be due to the translocation of GLUT4, which is more efficiently sequestered inside the cell and is present in much greater abundance than GLUT1. The cell type and isoform specificity of GLUT4 intracellular targeting were investigated by examining the subcellular distribution of GLUT1 and GLUT4 in cell types that are refractory to the effect of insulin on glucose transport. Rat GLUT4 was expressed in 3T3-L1 fibroblasts and HepG2 hepatoma cells by DNA-mediated transfection. Transfected 3T3-L1 fibroblasts over-expressing human GLUT1 exhibited increased glucose transport, and laser confocal immunofluorescent imaging of GLUT1 in these cells indicated that the protein was concentrated in the plasma membrane. In contrast, 3T3-L1 fibroblasts expressing GLUT4 exhibited no increase in transport activity, and confocal imaging demonstrated that this protein was targeted almost exclusively to cytoplasmic compartments. 3T3-L1 fibroblasts expressing GLUT4 were unresponsive to insulin with respect to transport activity, and no change was observed in the subcellular distribution of the protein after insulin administration. Immunogold labeling of frozen ultrathin sections revealed that GLUT4 was concentrated in tubulo-vesicular elements of the trans-Golgi reticulum in these cells. Sucrose density gradient analysis of 3T3-L1 homogenates was consistent with the presence of GLUT1 and GLUT4 in discrete cytoplasmic compartments. Immunogold labeling of frozen thin sections of HepG2 cells indicated that endogenous GLUT1 was heavily concentrated in the plasma membrane. Sucrose density gradient analysis of homogenates of HepG2 cells expressing rat GLUT4 suggested that GLUT4 is targeted to an intracellular location in these cells. The density of the putative GLUT4-containing cytoplasmic membrane vesicles was very similar in HepG2 cells, 3T3-L1 fibroblasts, 3T3-L1 adipocytes, and rat adipocytes. These data indicate that the intracellular trafficking of GLUT4 is isoform specific. Additionally, these observations support the notion that GLUT4 is targeted to its proper intracellular locale even in cell types that do not exhibit insulin-responsive glucose transport, and suggest that the machinery that regulates the intracellular targeting of GLUT4 is distinct from the factors that regulate insulin-dependent recruitment to the cell surface.
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PMID:Intracellular targeting of the insulin-regulatable glucose transporter (GLUT4) is isoform specific and independent of cell type. 165 37

A 58-year-old man, with primary hemochromatosis, cirrhosis, and diabetes mellitus treated with insulin developed hepatoma. As the tumor grew, he lost his dependence on insulin therapy and experienced episodes of hypoglycemia. His response to infuse insulin was studied using the euglycemic clamp technique. Insulin was infused at rates of 1 and 10 mu/kg/min. The insulin dose response curve was shifted to the left and at plasma insulin levels of 72 microU/ml, steady-state glucose consumption was 9.6 mg/kg/min, 50% more than in normals, and nearly three times greater than that in other cirrhotics. The insulin clearance rate was 4417 m1/m2/min, almost five and six times more than in normals and cirrhotics, respectively. Basal hepatic glucose production was 3.6 mg/kg/min, two and three times higher than in normal and in cirrhotic subjects, respectively. The decrease in amino acid during hyperinsulinemia was more than 30% higher than in normal and other cirrhotics. IFG-I and II levels were not elevated in this patient. Increased insulin sensitivity and increased insulin clearance and serum amino acid decrease in response to insulin in vivo, suggest that insulin responsive tissues are at last partially responsible for tumor hypoglycemia. The increased glucose disposal rate probably accounted for the disappearance of the diabetes.
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PMID:Case report: increased insulin sensitivity in tumor hypoglycemia in a diabetic patient: glucose metabolism in tumor hypoglycemia. 165 53

The present study investigates the effect of glucose on the gene expression of the hepatic glucoregulatory enzyme, phosphoenolpyruvate carboxykinase (PPrvck). By use of hepatocytes in culture and FAO hepatoma cells it could be demonstrated that glucose suppressed the effect of dibutyryl cyclic AMP (Bt2cAMP), glucocorticoids or both, to increase PPrvck mRNA and consequently PPrvck enzyme activity. Glucose had a dual effect; it reduced PPrvck gene transcription and it accelerated the rate of PPrvck mRNA degradation. The effect was specific for glucose, as glucose-related carbohydrates such as mannose, galactose and sorbitol were without effect on PPrvck mRNA. The repressive effect of glucose was limited to certain proteins; glucose had no effect on Bt2cAMP and glucocorticoid provoked induction of tyrosine aminotransferase (TAT). Also the pattern of mRNA in vitro translation products was virtually unaffected when FAO hepatoma cells were incubated either in the presence or absence of glucose, demonstrating the specificity of the effect of glucose on gene expression of selected proteins. In FAO hepatoma cells and in hepatocytes in culture, insulin, like glucose, also decreased PPrvck mRNA. While the effect of glucose and insulin was additive in FAO hepatoma cells, in primary hepatocytes in culture an effect of glucose by itself on PPrvck mRNA could only be demonstrated in the absence of insulin. Correspondingly also in vivo, the effect of glucose was demonstrated in the absence of insulin (provoked by streptozotocin diabetes); glucose application reduced the amount of hepatic PPrvck mRNA. To summarize, glucose is capable of suppressing the effect of glucocorticoids and Bt2cAMP on increasing the PPrvck mRNA level. The carbohydrate reduces the rate of PPrvck gene transcription and accelerates the rate of PPrvck mRNA degradation. While in FAO hepatoma cells the effect is evident in the presence of insulin, in hepatocytes in culture the effect of glucose cannot be demonstrated in the presence of insulin, questioning its role under physiological conditions.
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PMID:Transcriptional and post-transcriptional effects of glucose on liver phosphoenolpyruvate-carboxykinase gene expression. 166 21

Tumor uptake of 18F-fluorodeoxyglucose (FDG) was studied by dynamic positron emission tomography (PET) in 23 cases of hepatocellular carcinoma. The metabolic rate constants, K1 to K4, were generated by non-linear least square fitting method. We confirmed that K3 from the PET study significantly correlated with directly measured hexokinase activity of the cancer tissue. The region of HCC always had higher K3 values, which represents the hexokinase activity compared with the non-cancerous region. By FDG images, however, in 50% of cases the cancer region could not be clearly defined from the surrounding noncancerous hepatic tissue. These HCC cases without accumulation of FDG had a high ratio of K4/K3 (K4 represents glucose-6-phosphatase activity), which correlated well with the inverse ratio of FDG accumulating images on PET. According to the PET images which is represented by K4/K3 and the hexokinase activity which is represented by K3, we divided these 23 cases into three groups and retrospectively compared their survival rates. The groups with high K4/K3 (greater than or equal to 0.40) had longer survival than other groups. From the view point of glucose metabolism, the value of K4/K3 calculated from dynamic studies of FDG-PET may represent the functional differentiation of HCC.
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PMID:[Can fluorodeoxyglucose-positron emission tomography evaluate the functional differentiation of hepatocellular carcinoma]. 166 76


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