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 effects of fasting on the rate of fatty acid synthesis, the properties of the mitochondrial citrate transporter and on pyruvate dehydrogenase activity were investigated in "poorly-differentiated" tmorris hepatoma 7777 and in host liver preparations. The properties of the citrate transporter from hepatoma mitochondria were similar to those of host liver mitochondria, with the exception that the Km for the liver mitochondrial citrate transporter was 248 plus or minus 20 mu M while that in hepatoma mitochondria was less than 75 mu M. The acid-insoluble CoA content was 180 plus or minus 20 pmol/mg protein in the hepatoma and remained essentially unchanged in the fasted state, while the acid-insoluble CoA levels in livers from fed rats was 720 plus or minus 80 pmol/mg protein and were increased to 1050 plus or minus 50 pmol/mg protein during fasting. After a 36-h fast, the rate of lipogenesis and the percentage of pyruvate dehydrogenase present in the active form were each decreased by approximately 80% in host liver preparations. In contrast, the rate of lipogenesis by hepatoma slices did not decrease during fasting, and essentially all pyruvate dehydrogenase present was in the active form of hepatomas obtained from either fed or fasted animals. Implications concerning the identification of possible regulatory sites in the control of lipogenesis were discussed in relation to the above observations.
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PMID:Effects of fasting on the control of fatty-acid synthesis in hepatoma 7777 and host liver. Role of long-chain fatty acyl-CoA,, the mitochondrial citrate transporter and pyruvate dehydrogenase activity. 16 42

Kinetic studies of Morris 7777 hepatoma mitochondrial NAD(P) malic enzyme were consistent with an ordered mechanism where NAD adds to the enzyme before malate and dissociation of NADH from the enzyme is rate-limiting. In addition to its active site, malate apparently also associates with a lower affinity with an activator site. The activator fumarate competes with malate at the activator site and facilitates dissociation of NADH from the enzyme. The ratio of NAD(P) malic enzyme to malate dehydrogenase activity in the hepatoma mitochondrial extract was found to be too low, even in the presence of known inhibitors of malate dehydrogenase, to account for the known ability of NAD(P) malic enzyme to intercept exogenous malate from malate dehydrogenase in intact tumor mitochondria (Moreadith, R.W., and Lehninger, A.L. (1984) J. Biol. Chem. 259, 6215-6221). However, NAD(P) malic enzyme may be able to intercept exogenous malate because according to the present results, it can associate with the pyruvate dehydrogenase complex, which could localize NAD(P) malic enzyme in the vicinity of the inner mitochondrial membrane. The activity levels of some key metabolic enzymes were found to be different in Morris 7777 mitochondria than in liver or mitochondria of other rapidly dividing tumors. These results are discussed in terms of differences among tumors in their ability to utilize malate, glutamate, and citrate as respiratory fuels.
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PMID:Kinetics and regulation of hepatoma mitochondrial NAD(P) malic enzyme. 158 26

The methods to detect antimitochondrial antibodies (AMAs), which are characteristically positive in primary biliary cirrhosis (PBC), have some problems in technical difficulty, sensitivity and specificity. Based on the finding that one of the major antigens corresponding to AMAs was the E2 component of pyruvate dehydrogenase complex (PDH), a very simple enzyme-linked immunosorbent assay (ELISA) to detect anti-PDH antibody (anti-PDH) has been developed in this study. Among 68 patients with PBC, IgG class anti-PDH and IgM class anti-PDH were detected in 64 patients (94.1%) and in 55 patients (80.8%), respectively, while only three cases (4.4%) were both negative. Mean optical densities (O.D.) of sera from patients with PBC were 0.536 +/- 0.386 (mean +/- SD) in IgG class and 0.308 +/- 0.342 in IgM class. No positive cases were detected in the following patients by this ELISA: 20 patients with acute viral hepatitis, 24 with chronic persistent hepatitis, 32 with chronic active hepatitis, 19 with liver cirrhosis, 19 with hepatocellular carcinoma, 19 with acute intrahepatic cholestasis, 10 with autoimmune hepatitis, and six with systemic lupus erythematosus. Among nine AMAs negative cases with PBC by conventional indirect immunofluorescence (IF) assay, seven cases were found to be positive by this ELISA. The inter-assay coefficient of the variation of this method ranged from 4.9% to 5.8% and the intra-assay coefficient of variation from 3.8% to 5.1%. Therefore, this ELISA is useful for diagnosis of PBC.
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PMID:Detection of anti-pyruvate dehydrogenase complex antibody in primary biliary cirrhosis by an enzyme-linked immunosorbent assay. 221 Feb 21

Reuber H-35 rat hepatoma cells respond to physiological levels of insulin as a growth factor. Glucocorticoids antagonize this response. A chemical mediator of insulin action which activates mitochondrial pyruvate dehydrogenase has also been isolated from these cells. The present report demonstrates that if the H35 cells are incubated with glucocorticoid before treatment with insulin, they produce not only the stimulator, but also inhibitory mediator. Cells exposed to the glucocorticoid but not to insulin do not produce the inhibitory mediator. Therefore, insulin interaction with the cell is necessary to elicit this negative modifier of pyruvate dehydrogenase. A time course of the response suggests that the effect of the glucocorticoid is time dependent. The inhibitory mediator can be separated from the stimulatory mediator by molecular sieve chromatography. These results suggest a biochemical basis for glucocorticoid-mediated insulin resistance.
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PMID:Dexamethasone permits the release of an inhibitor of pyruvate dehydrogenase from Reuber H-35 hepatoma cells in response to insulin. 299 Aug 58

The effects of putative insulin mediators on the pyruvate dehydrogenase (PDH) activity of intact mitochondria isolated from rat liver were investigated. The mitochondria were judged intact on the basis of electron microscopic examination and demonstrated respiratory control. Only mitochondria having respiratory control ratios of greater than 4, using succinate as a substrate, were used in these studies. Addition of physiologic concentrations of insulin to these mitochondria caused stimulation of PDH activity, attributed to generation of an insulin mediator from plasma membranes contaminating the mitochondrial preparation. Exogenous plasma membranes from rat adipocytes or liver caused further stimulation of PDH activity, which was proportional to the amount of plasma membranes added. Addition of insulin to the mixture of mitochondria and plasma membranes stimulated PDH still further. The stimulation was proportional to the insulin concentration, with maximal effects observed at 50 microU/ml insulin. Partially purified mediators from liver, muscle, H4-II-E hepatoma cells, and IM9 lymphocytes also stimulated PDH activity in intact mitochondria. Mediators prepared from insulin-treated liver, muscle, and cultured hepatoma cells stimulated PDH more than did mediators from the corresponding untreated source. Mediator from insulin-treated IM9 lymphocytes stimulated PDH less than did mediator from untreated IM9 lymphocytes. These findings are consistent with the known effects of insulin on these tissues and with the reported effects of the various mediators on PDH activity in non-intact mitochondria. These observations support the proposal that these mediators are physiologically significant modulators of insulin's effects on PDH activity.
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PMID:Insulin mediator stimulates pyruvate dehydrogenase of intact liver mitochondria. 388 May 52

Studies with a subcellular system demonstrated that the interaction of insulin with the adipocyte plasma membrane resulted in the generation from the plasma membrane of a mediator that activated mitochondrial pyruvate dehydrogenase (EC 1.2.4.1). The insulin-sensitive chemical mediator from the plasma membrane has been partially characterized. It has a molecular weight of 1000-1500. The chemical mediator has been extracted from skeletal muscle, adipocytes, hepatoma cells, and IM-9 lymphocytes. Insulin increased the amount or activity of the mediator in the first three cell types, whereas insulin decreased the activity or amount of the mediator in IM-9 lymphocytes. These insulin-induced variations were consistent with the biological responses of these cells to insulin treatment. The activities of insulin-sensitive enzymes, including pyruvate dehydrogenase, adipocyte low Km 3':5'-cyclic-AMP phosphodiesterase (EC 3.1.4.17), and adipocyte plasma membrane [Ca2+ + Mg2+]-ATPase were shown to be altered by the chemical mediator. The mediator may act by altering various protein kinases and phosphoprotein phosphatases that modulate the state of phosphorylation and activity of these enzyme systems. The existence of two mediators is proposed. The first may mediate dephosphorylation of various substrates, and the second may influence phosphorylation.
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PMID:Chemical mediator or mediators of insulin action: response to insulin and mode of action. 628 77

An insulin-sensitive subcellular system was developed from rat adipocytes consisting of plasma membranes and mitochondria. Direct addition of insulin, concanavalin A or anti-insulin receptor antibody to this system resulted in the production of a mediator substance from the plasma membrane that caused dephosphorylation of the alpha subunit of pyruvate dehydrogenase in the mitochondria with concomitant activation of the enzyme. The mediator activated pyruvate dehydrogenase by activating the pyruvate dehydrogenase phosphatase and not by inhibiting the pyruvate dehydrogenase kinase. This was similar to the mechanism by which insulin causes activation of the enzyme in the intact cell. The insulin-sensitive mediator material from the adipocyte plasma membrane was acid-stable with a molecular weight of 1,000 to 1,500. Our laboratory has shown that the mediator that activates pyruvate dehydrogenase was present in intact adipocytes, hepatoma cells, and IM-9 lymphocytes. Insulin altered the amount or activity of the mediator consistent with the effect of the hormone on the cell. Other laboratories have shown similar effects on skeletal muscle and liver. We have shown the mediator to mimic insulin action on the low Km cyclic adenosine monophosphate (AMP) phosphodiesterase and the (calcium++-magnesium++)-adenosine triphosphatase (Ca++-Mg++)-ATPase of adipocyte plasma membranes in addition to pyruvate dehydrogenase. Other laboratories have shown the mediator to activate glycogen synthase. A body of direct and indirect evidence exists that demonstrates that more than one mediator exists. The chemical nature of the mediator is unknown but probably represents a new family of intracellular mediators of hormone action. These mediators may have clinical relevance in postreceptor defects of obesity and type II diabetes (noninsulin-dependent diabetes mellitus).
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PMID:The chemical mediators of insulin action: possible targets for postreceptor defects. 633 85

The pathway of fat oxidation in two experimental hepatomas was studied in order to demonstrate that a specific deficit in the energy metabolism of a tumor might contribute to the cachexia of the host. Forty-eight male Buffalo rats were divided into four groups of 12 each. One group was implanted s.c. with Morris hepatoma 7777 and one group was implanted with Morris hepatoma 7800, whereas the other two groups served as controls. All groups were fed standard rat chow diet ad libitum until the tumors reached 2 cm in diameter. The animals were then fasted for 24 hr prior to sacrifice and excision of tumor and liver for assays. During the period of tumor growth, the animals bearing the 7777 hepatoma lost weight, but the weight of the 7800 hepatoma-bearing rats did not differ significantly from that of the control animals. The livers of both groups of animals showed evidence of fatty acid oxidation in vivo and in vitro, and, as expected, during fasting, pyruvate dehydrogenase was inactivated and the rate of fatty acid synthesis was low. A qualitatively similar picture was seen with the better-differentiated 7800 hepatoma. In contrast, the 7777 hepatoma exhibited low levels of fatty acyl coenzyme CoA, no appreciable activity of carnitine palmitoyl transferase and fortified homogenates of the tumor were unable to oxidize palmitate. In keeping with these observations, pyruvate dehydrogenase remained in the active form, and fatty acid synthesis continued unabated in the fasted state in these tumors. Ketone bodies could not be oxidized by fortified homogenates of the liver or by either tumor, probably due to the lack of 3-ketoacid thiotransferase, which was undetectable in these tissues. We hypothesize that flow-through pyruvate dehydrogenase during fasting in Morris hepatoma 7777, occurring as a result of the defect in fat oxidation, contributes to the weight loss of these animals.
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PMID:Regulation of energy metabolism in Morris hepatoma 7777 and 7800. 724 42

The signal transduction pathway involved in the activation of pyruvate dehydrogenase (PDH) by insulin is still unknown. In this study, we have examined the possible involvement of protein kinase C (PKC) in the process. In addressing this question, we examined (1) the insulin-like effects of the PKC activator 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) on the PDH complex, (2) the effects of various PKC inhibitors on the PDH activation by insulin, and (3) the response of PKC-depleted cells to insulin. We used as an experimental model Zajdela hepatoma cultured (ZHC) cells, which have been demonstrated to be responsive to physiological doses of insulin. Half-maximal and maximal stimulations of the PDH complex by insulin were observed at 0.05 and 5 nmol/L, respectively. Stimulation of PDH activity by insulin (5 nmol/L) occurred within 5 minutes of incubation and was maximal (+70%) at 7.5 minutes. In the presence of PMA (162 nmol/L), enzyme activity increased within 30 seconds, was maximal (+90%) at 5 minutes, and was no longer detectable after 10 minutes. Total PDH activity was unchanged by insulin or PMA treatment. The effects of PMA and insulin on basal PDH activity were not additive. Moreover, various inhibitors of PKC--staurosporine, sphingosine, acridine orange--completely blocked the stimulation of PDH activity induced by insulin or PMA. A 17-hour treatment of ZHC cells with 500 nmol/L PMA efficiently downregulated PKC, as attested by the marked decrease in the enzyme activity and the loss of phorbol 12,13-dibutyrate binding to intact cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for a role of protein kinase C in the activation of the pyruvate dehydrogenase complex by insulin in Zajdela hepatoma cells. 805 43

A case of chronic hepatitis C at the pre-cirrhotic stage complicated with hepatocellular carcinoma is reported. The patient, a 64 year old female, showed elevated levels of serum alkaline phosphatase and immunoglobulin M. Antimitochondrial antibodies were negative by indirect immunofluorescence. Western blotting using beef heart mitochondria and recombinant polypeptides coding for mitochondrial antigens revealed that the patient's serum was positive only for the E2-subunit of the branched chain ketoacid dehydrogenase complex. In the non-neoplastic liver, chronic non-suppurative cholangitis surrounded by epithelioid granuloma, resembling the granulomatous destructive cholangitis of primary biliary cirrhosis, was found. The damaged bile ducts were immunohistochemically minimally positive or ambiguous for HLA-DR, and their expression of the E2-subunit of the pyruvate dehydrogenase complex E2 (PDC-E2) was diffuse or granular, and not typical of primary biliary cirrhosis. There was no bile duct loss, and orcein-positive copper binding granules reflecting chronic cholestasis were negative in periportal hepatocytes. The overall features in this case were consistent with primary biliary cirrhosis presenting an infrequent profile of antimitochondrial antibodies and atypical expression of HLA-DR and PDC-E2 on biliary epithelial cells, with late superimposition on chronic hepatitis C. However, it is also possible that this is a case of chronic hepatitis C with hepatitis-associated bile duct damage accompanied by granulomatous reaction. Either way, this case raises new diagnostic issues in the differential diagnosis of chronic liver diseases presented with granulomatous cholangitis.
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PMID:Granulomatous cholangitis in chronic hepatitis C: a new diagnostic problem in liver pathology. 872 56


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