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 transcription factor FKHR (FOXO1a) is regulated by protein kinase B (PKB) and insulin controls the expression of hepatic genes like glucose-6-phosphatase (G6Pase) at least in part via these proteins. However, insulin is known to activate several pathways and it is therefore difficult to establish which effects of the hormone are attributed to PKB and FKHR signaling. The aim of the present study was the generation of cellular models which allow the specific analysis of molecular events controlled by PKB and FKHR, respectively. We generated two H4IIEC3 rat hepatoma cell lines stably expressing either a hydroxytamoxifen-regulatable form of PKB (myristoylated PKB estrogen receptor chimera; MER-PKB) or FKHR (FKHR estrogen receptor chimera; FKHR-ER) by retroviral infection and determined the regulation of the G6Pase transcript by Northern blotting and enzyme assays. Activation of the regulatable PKB fusion protein almost completely reduced the dexamethasone/cAMP-stimulated G6Pase mRNA levels comparable to the effect of insulin. In contrast, stimulation of FKHR-ER with tamoxifen increased the expression of the dexamethasone/cAMP-induced G6Pase mRNA and the G6Pase enzymatic activity about 2.5- to 3-fold. The present data demonstrate that activation of PKB is sufficient to mimic the effect of insulin on the expression of G6Pase and that FKHR acts as an activator of the G6Pase gene indicating that the established cellular models are suitable for the specific analysis of downstream targets of these signaling molecules. Therefore, these cell systems might serve as useful tools for the development of anti-diabetic drugs.
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PMID:Cellular models for the analysis of signaling by protein kinase B and the forkhead transcription factor FKHR (Foxo1a). 1525 69

We present a case of a 73 year old man, who lost 12 kg of weight in one month, had abdominal pain and progressive hepatic failure. A MRI and liver ultrasound were performed and, with the patient's symptoms, hepatocellular carcinoma Vs metastatic liver was suspected. A PET-FDG was performed and the images showed hepatomegaly and splenomegaly, without other findings of interest. FDG distribution in the liver was homogeneous. The patient was diagnosed of hepatocellular carcinoma after liver biopsy. FDG-PET detects only 50 % to 70 % of hepatocellular carcinomas due to varying degrees of activity of the enzyme glucose-6-phosphatase in these tumors. This paper reviews the literature on this type of situations.
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PMID:[FDG-PET in hepatocellular carcinoma. Based on one case]. 1545 Jan 42

The first steps of glucose metabolism are carried out by members of the families of GLUTs (glucose transporters) and HKs (hexokinases). Previous experiments using the inhibitor of glucose transport, CB (cytochalasin B), revealed that compartmentalization of GLUTs and HKs is a major factor in the control of glucose uptake in L6 myotubes [Whitesell, Ardehali, Printz, Beechem, Knobel, Piston, Granner, Van Der Meer, Perriott and May (2003) Biochem. J. 370, 47-56]. In the present paper, we evaluate compartmentalization of GLUTs and HKs in a hepatoma cell line, H4IIE, which is characterized by excess GLUT activity, HKI in a particulate and a cytosolic fraction, and insignificant G6Pase (glucose-6-phosphatase) activity. The measured activity of glucose transport exceeded the rate of phosphorylation approx. 30-fold. Treatment with 25 microM CB (K(i) approximately 3 microM in H4IIE cells) paradoxically increased the excess of GLUTs over phosphorylation (GLUTs are inhibited 80%, while phosphorylation is inhibited 98%). The global relationships of the data could be reconciled most simply by a two-compartment model. In this model, phosphorylation of glucose is carried out by a subset of HK molecules supplied by a subset of GLUTs that are more sensitive to CB than the other GLUTs. The agent, DCC (dicyclohexylcarbodi-imide) caused HKI to translocate from the particulate compartment to the cytosolic compartment and potently inhibited glucose phosphorylation. The particulate compartment may represent the mitochondria, to which the more CB-sensitive GLUTs may control the transport of glucose.
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PMID:Compartmentalization of transport and phosphorylation of glucose in a hepatoma cell line. 1547 66

Metformin is thought to decrease blood glucose levels by reducing hepatic glucose output. To elucidate the pharmacological action of metformin on hepatic glucose production, we examined its effect on the gene expression of glucose-6-phosphatase (G6Pase), a key enzyme of gluconeogenesis, in H4IIE rat hepatoma cell line by RT-PCR and quantitative real-time PCR. Metformin suppressed dexamethasone/cAMP-induced expression of G6Pase mRNA in a dose dependent manner, its maximum effect being observed at 2 mM (79.3% inhibition, P<0.05). Pretreatment with the PI3-kinase inhibitor wortmannin, the MEK-1 inhibitor PD98059 or the protein kinase C inhibitor GF109203X had no effect on suppressed G6Pase expression by metformin. Moreover, metformin did not stimulate Akt phosphorylation. In the present study, we demonstrate that metformin suppresses G6Pase mRNA expression by a mechanism that is independent of the activation of PI3-kinase, Akt, MAP kinase and protein kinase C pathway in hepatocytes.
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PMID:Metformin-induced suppression of glucose-6-phosphatase expression is independent of insulin signaling in rat hepatoma cells. 1570 36

Glucose-6-phosphatase (G6Pase) catalyzes the release of glucose from glucose 6-phosphate. This enzyme was mainly studied in the liver, but while detected in the small intestine little is known about the regulation of its intestinal expression. This study describes the mechanisms of the glucose-dependent regulation of G6Pase expression in intestinal cells. Results obtained in vivo and in Caco-2/TC7 enterocytes showed that glucose increases the G6Pase mRNA level. In Caco-2/TC7 cells, glucose stabilized G6Pase mRNA and activated the transcription of the gene, meaning that glucose-dependent G6Pase expression involved both transcriptional and post-transcriptional mechanisms. Reporter-gene studies showed that, although the -299/+57 region of the human G6Pase promoter was sufficient to trigger the glucose response in the hepatoma cell line HepG2, the -1157/-1133 fragment was required for maximal activation of glucose-6-phosphatase gene transcription in Caco-2/TC7 cells. This fragment binds the aryl receptor nuclear translocator (ARNT), cAMP-responsive element-binding protein, and upstream stimulatory factor transcription factors. The DNA binding activity of these transcription factors was increased in nuclear extracts of differentiated cells from the intestinal villus of mice fed sugar-rich diets as compared with mice fed a no-sugar diet. A direct implication of ARNT in the activation of G6Pase gene transcription by glucose has been observed in Caco-2/TC7 cells using RNA interference experiments. These results support a physiological role for G6Pase in the control of nutrient absorption in the small intestine.
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PMID:Intestinal glucose-dependent expression of glucose-6-phosphatase: involvement of the aryl receptor nuclear translocator transcription factor. 1576 53

The effect of ethanolic extract of Terminalia arjuna bark on carbohydrate metabolizing enzymes of N-nitrosodiethylamine induced hepatocellular carcinoma in Wistar albino rats were studied. The plasma and liver glycolytic enzymes such as hexokinase, phosphoglucoisomerase, aldolase were significantly increased in cancer induced animals while glyconeogenic enzyme, glucose-6-phosphatase was decreased. These enzymes were reverted significantly to near normal range in treated animals after oral administration of T. arjuna for 28 days. The modulation of the enzymes constitute the depletion of energy metabolism leads to inhibition of cancer growth. This inhibitory activity may be due to the anticancer activity of constituents present in the ethanolic extract of T. arjuna.
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PMID:Efficacy of Terminalia arjuna (Roxb.) on N-nitrosodiethylamine induced hepatocellular carcinoma in rats. 1581 14

Glucose-6-phosphatase catalyzes the final step in the gluconeogenic and glycogenolytic pathways. Glucocorticoids stimulate glucose-6-phosphatase catalytic subunit (G6Pase) gene transcription and studies performed in H4IIE hepatoma cells demonstrate the presence of a glucocorticoid response unit (GRU) in the proximal G6Pase promoter. In vitro deoxyribonuclease I footprinting analyses show that the glucocorticoid receptor binds to three glucocorticoid response elements (GREs) in the -231 to -129 promoter region and transfection results indicate all three contribute to glucocorticoid induction of G6Pase gene transcription. Furthermore, binding sites for hepatocyte nuclear factor-1 and -4, CRE binding factors, and FKHR (FOXO1a) are required for the full glucocorticoid response. Chromatin immunoprecipitation assays show that dexamethasone treatment stimulates glucocorticoid receptor and FKHR binding to the endogenous G6Pase promoter. Surprisingly, although glucocorticoids stimulate G6Pase gene transcription, deoxyribonuclease I footprinting and transfection analyses demonstrate the presence of a negative GRE and an associated negative accessory factor element in the -271 to -225 promoter region, which inhibit the glucocorticoid response. This appears to be the first report of a promoter that contains both positive and negative GREs, which function within the same cellular environment. We hypothesize that targeted signaling to the negative accessory element within the GRU may provide tight regulation of the glucocorticoid stimulation.
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PMID:The glucose-6-phosphatase catalytic subunit gene promoter contains both positive and negative glucocorticoid response elements. 1603 30

Insulin is a key hormone that controls glucose homeostasis. In liver, insulin suppresses gluconeogenesis by inhibiting the transcriptions of phosphoenolpyruvate carboxylase (PEPCK) and glucose-6-phosphatase (G6Pase) genes. In insulin resistance and type II diabetes there is an elevation of hepatic gluconeogenesis, which contributes to hyperglycemia. To search for novel genes that negatively regulate insulin signaling in controlling metabolic pathways, we screened a cDNA library derived from the white adipose tissue of ob/ob mice using a reporter system comprised of the PEPCK promoter placed upstream of the alkaline phosphatase gene. The mitogen-activated dual specificity protein kinase phosphatase 3 (MKP-3) was identified as a candidate gene that antagonized insulin suppression on PEPCK gene transcription from this screen. In this study, we showed that MKP-3 was expressed in insulin-responsive tissues and that its expression was markedly elevated in the livers of insulin-resistant obese mice. In addition, MKP-3 can activate PEPCK promoter in synergy with dexamethasone in hepatoma cells. Furthermore, ectopic expression of MKP-3 in hepatoma cells by adenoviral infection increased the expression of PEPCK and G6Pase genes and led to elevated glucose production. Taken together, our data strongly suggests that MKP-3 plays a role in regulating gluconeogenic gene expression and hepatic gluconeogenesis. Therefore, dysregulation of MKP-3 expression and/or function in liver may contribute to the pathogenesis of insulin resistance and type II diabetes.
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PMID:Dual specificity MAPK phosphatase 3 activates PEPCK gene transcription and increases gluconeogenesis in rat hepatoma cells. 1612 24

Adiponectin plays important roles in regulating insulin sensitivity and atherogenesis. Adiponectin has been shown to suppress hepatic glucose production in rodents. It has not been reported whether ectopically expressed adiponectin could regulate glucose metabolism in cultured hepatocyte-like cells. In the current study, the effect of adiponectin on glucose production was analyzed by ectopically expressing the protein in hepatoma H4IIE cells using an adenovirus delivery system to generate both human full-length and the globular domain of the protein. Expression of adiponectin in hepatoma H4IIE cells, in the absence of insulin, suppressed expression of the genes encoding glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, rate-limiting enzymes in the gluconeogenic pathway. Furthermore, expression of adiponectin in H4IIE cells suppressed glucose production from lactate and pyruvate. Purified recombinant human adiponectin also reduced glucose production in H4IIE cells and in rat primary hepatocytes in the absence of insulin. These data suggest that adiponectin protein could exert its function independent of the presence of insulin in these culture systems.
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PMID:Adiponectin represses gluconeogenesis independent of insulin in hepatocytes. 1623 52

Liver X receptor (LXR) paralogues alpha and beta (LXRalpha and LXRbeta) are members of the nuclear hormone receptor family and have oxysterols as endogenous ligands. LXR activation reduces hepatic glucose production in vivo through the inhibition of transcription of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (G6Pase). In the present study, we investigated the molecular mechanisms involved in the regulation of G6Pase gene expression by LXR. Both T0901317, a synthetic LXR agonist, and the adenoviral overexpression of either LXRalpha or LXRbeta suppressed G6Pase gene expression in H4IIE hepatoma cells. However, compared to the suppression of G6Pase expression seen by insulin, the decrease of G6Pase mRNA by LXR activation was delayed and was blocked by cycloheximide, an inhibitor of protein synthesis. These observations, together with the absence of a conserved LXR-binding element within the G6Pase promoter, suggest an indirect inhibition of G6Pase gene expression by liver X receptors.
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PMID:Evidence for an indirect transcriptional regulation of glucose-6-phosphatase gene expression by liver X receptors. 1625 38


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