Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.3.9 (glucose-6-phosphatase)
 3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin responsive H4IIEC3 rat hepatoma cell line (H4 cells) was used in order to determine the role of the transcription factor FKHR in the regulation of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Both PEPCK and G6Pase contain putative FKHR binding sites in their promoter sequence. Using a retroviral expression system, we stably overexpressed FKHR in H4-cells. FKHR was phosphorylated in a PI 3-kinase- and Akt-dependent manner, and was translocated from the nucleus to the cytoplasm in response to insulin. Furthermore, overexpression of FKHR markedly increased the expression of the catalytic subunit of G6Pase (basal about 2.5-fold, dexamethasone/cAMP stimulated about fivefold, respectively). In contrast, both basal and dexamethasone/cAMP-induced levels of PEPCK mRNA were unaffected by FKHR-overexpression. These data suggest a specific function for FKHR in the regulation of hepatic gluconeogenesis at the level of G6Pase, but not PEPCK gene expression.
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PMID:Differential regulation of endogenous glucose-6-phosphatase and phosphoenolpyruvate carboxykinase gene expression by the forkhead transcription factor FKHR in H4IIE-hepatoma cells. 1146 35

The regulation of glucose-6-phosphatase (G-6-Pase) catalytic subunit and glucose 6-phosphate (G-6-P) transporter gene expression by insulin in conscious dogs in vivo and in tissue culture cells in situ were compared. In pancreatic-clamped, euglycemic conscious dogs, a 5-h period of hypoinsulinemia led to a marked increase in hepatic G-6-Pase catalytic subunit mRNA; however, G-6-P transporter mRNA was unchanged. In contrast, a 5-h period of hyperinsulinemia resulted in a suppression of both G-6-Pase catalytic subunit and G-6-P transporter gene expression. Similarly, insulin suppressed G-6-Pase catalytic subunit and G-6-P transporter gene expression in H4IIE hepatoma cells. However, the magnitude of the insulin effect was much greater on G-6-Pase catalytic subunit gene expression and was manifested more rapidly. Furthermore, cAMP stimulated G-6-Pase catalytic subunit expression in H4IIE cells and in primary hepatocytes but had no effect on G-6-P transporter expression. These results suggest that the relative control strengths of the G-6-Pase catalytic subunit and G-6-P transporter in the G-6-Pase reaction are likely to vary depending on the in vivo environment.
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PMID:Selective tonic inhibition of G-6-Pase catalytic subunit, but not G-6-P transporter, gene expression by insulin in vivo. 1155 47

Blood glucose levels are maintained by the balance between glucose uptake by peripheral tissues and glucose secretion by the liver. Gluconeogenesis is strongly stimulated during fasting and is aberrantly activated in diabetes mellitus. Here we show that the transcriptional coactivator PGC-1 is strongly induced in liver in fasting mice and in three mouse models of insulin action deficiency: streptozotocin-induced diabetes, ob/ob genotype and liver insulin-receptor knockout. PGC-1 is induced synergistically in primary liver cultures by cyclic AMP and glucocorticoids. Adenoviral-mediated expression of PGC-1 in hepatocytes in culture or in vivo strongly activates an entire programme of key gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, leading to increased glucose output. Full transcriptional activation of the PEPCK promoter requires coactivation of the glucocorticoid receptor and the liver-enriched transcription factor HNF-4alpha (hepatic nuclear factor-4alpha) by PGC-1. These results implicate PGC-1 as a key modulator of hepatic gluconeogenesis and as a central target of the insulin-cAMP axis in liver.
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PMID:Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. 1155 65

Type 2 diabetes is characterized by the inability of insulin to suppress glucose production in the liver and kidney. Insulin inhibits glucose production by indirect and direct mechanisms. The latter result in transcriptional suppression of key gluconeogenetic and glycogenolytic enzymes, phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6p). The transcription factors required for this effect are incompletely characterized. We report that in glucogenetic kidney epithelial cells, Pepck and G6p expression are induced by dexamethasone (dex) and cAMP, but fail to be inhibited by insulin. The inability to respond to insulin is associated with reduced expression of the forkhead transcription factor Foxo1, a substrate of the Akt kinase that is inhibited by insulin through phosphorylation. Transduction of kidney cells with recombinant adenovirus encoding Foxo1 results in insulin inhibition of dex/cAMP-induced G6p expression. Moreover, expression of dominant negative Foxo1 mutant results in partial inhibition of dex/cAMP-induced G6p and Pepck expression in primary cultures of mouse hepatocyes and kidney LLC-PK1-FBPase(+) cells. These findings are consistent with the possibility that Foxo1 is involved in insulin regulation of glucose production by mediating the ability of insulin to decrease the glucocorticoid/cAMP response of G6p.
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PMID:The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. 1169 81

The expression of glucose-6-phosphatase (G6Pase) mRNA is repressed by insulin and stimulated by cAMP and dexamethasone, with the insulin effect dominant. Both lipids and glucose increase the expression of G6Pase mRNA under conditions in which insulin is either absent or at basal levels. The aim of the present study was to investigate dietary nutrient regulation of G6Pase mRNA and protein under postprandial conditions. Male rats (n = 6-8/group) were deprived of food for 48 h and then either remained food deprived (FD) or were refed diets containing 68% cornstarch and 12% corn oil (ST; % energy), 68% sucrose and 12% corn oil (SU) or 35% cornstarch and 45% corn oil (HF) for 3 h. Rats were anesthetized, blood was drawn from the portal vein, and the liver was removed and immediately processed for subsequent analyses. Energy intake over the 3-h refeeding period did not differ among groups (209 +/- 25 kJ). Portal vein glucose and insulin were 5.0 +/- 0.2 mmol/L and 90 +/- 18 pmol/L, respectively, in FD rats and were not significantly different among the refed groups (14.5 +/- 1.2 mmol/L and 1302 +/- 154 pmol/L, respectively). Compared with the FD rats, G6Pase mRNA was approximately 50% lower in ST and HF groups, whereas it was approximately 1.6 fold higher in SU-refed rats (P < 0.05). G6Pase activity in whole liver homogenates was lower in ST and HF rats than in FD and SU rats. Insulin receptor substrate (IRS) phosphorylation, IRS-association with phosphatidylinositol 3 (PI3)-kinase and activation of protein kinase B (PKB) were not significantly different among the refed groups. However, glycogen synthase kinase-3alpha phosphorylation was lower and cAMP response element binding protein (CREB) phosphorylation was higher in SU rats than in ST and HF refed groups. Thus, the postprandial environment after ingestion of sucrose appears to overcome the dominant effects of insulin on G6Pase mRNA, perhaps via cellular changes that reduce phosphorylation of, and therefore activate, glycogen synthase kinase-3alpha.
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PMID:Glucose-6-phosphatase activity is not suppressed but the mRNA level is increased by a sucrose-enriched meal in rats. 1251 63

We recently compared the regulation of glucose-6-phosphatase (G-6-Pase) catalytic subunit and glucose 6-phosphate (G-6-P) transporter gene expression by insulin in conscious dogs in vivo (Hornbuckle LA, Edgerton DS, Ayala JE, Svitek CA, Neal DW, Cardin S, Cherrington AD, and O'Brien RM. Am J Physiol Endocrinol Metab 281: E713-E725, 2001). In pancreatic-clamped, euglycemic conscious dogs, a 5-h period of hypoinsulinemia led to a marked increase in hepatic G-6-Pase catalytic subunit mRNA; however, G-6-P transporter mRNA was unchanged. Here, we demonstrate, again using pancreatic-clamped, conscious dogs, that glucagon is a candidate for the factor responsible for this selective induction. Thus glucagon stimulated G-6-Pase catalytic subunit but not G-6-P transporter gene expression in vivo. Furthermore, cAMP stimulated endogenous G-6-Pase catalytic subunit gene expression in HepG2 cells but had no effect on G-6-P transporter gene expression. The cAMP response element (CRE) that mediates this induction was identified through transient transfection of HepG2 cells with G-6-Pase catalytic subunit-chloramphenicol acetyltransferase fusion genes. Gel retardation assays demonstrate that this CRE binds several transcription factors including CRE-binding protein and CCAAT enhancer-binding protein.
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PMID:Selective stimulation of G-6-Pase catalytic subunit but not G-6-P transporter gene expression by glucagon in vivo and cAMP in situ. 1472 27

Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the initial step in hepatic gluconeogenesis. In the fasted state, PEPCK gene expression is activated by glucagon (via cAMP) and glucocorticoids. Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) plays an important role in energy homeostasis and is considered to be a key regulator of hepatic gluconeogenesis in response to fasting. It is not clear whether PGC-1alpha is obligatory for the activation of the transcription program of gluconeogenic genes, or whether it amplifies an existing process. H4IIE hepatoma cells were used to address this key point. These cells respond appropriately to all of the hormones involved in the regulation of gluconeogenic genes, yet they are devoid of PGC-1alpha. Also, these hormone responses occur in the absence of ongoing protein synthesis, so the necessary complement of transcription factors exists in untreated cells. However, exogenous expression of PGC-1alpha in these cells does enhance basal and hormone-induced expression of the PEPCK and glucose-6-phosphatase genes. Mutational analyses of the PEPCK gene promoter reveal that one element in the PEPCK gene promoter, glucocorticoid accessory factor 3, which binds chicken ovalbumin upstream promoter-transcription factor, is of particular importance. Taken together, these data suggest that, under chronic fasting conditions, i.e. when high levels of cAMP and glucocorticoids induce PGC-1alpha expression, this coactivator markedly amplifies PEPCK gene expression and gluconeogenesis.
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PMID:Peroxisome proliferator-activated receptor gamma coactivator-1alpha, as a transcription amplifier, is not essential for basal and hormone-induced phosphoenolpyruvate carboxykinase gene expression. 1504 97

The key insulin-regulated gluconeogenic enzyme G6Pase (glucose-6-phosphatase) has an important function in the control of hepatic glucose production. Here we examined the inhibition of G6Pase gene transcription by TNF (tumour necrosis factor) in H4IIE hepatoma cells. TNF decreased dexamethasone/dibtuyryl cAMP-induced G6Pase mRNA levels. TNFalpha, but not insulin, led to rapid activation of NFkappaB (nuclear factor kappaB). The adenoviral overexpression of a dominant negative mutant of IkappaBalpha (inhibitor of NFkappaB alpha) prevented the suppression of G6Pase expression by TNFalpha, but did not affect that by insulin. The regulation of G6Pase by TNF was not mediated by activation of the phosphoinositide 3-kinase/protein kinase B pathway, extracellular-signal-regulated protein kinase or p38 mitogen-activated protein kinase. Reporter gene assays demonstrated a concentration-dependent down-regulation of G6Pase promoter activity by the transient overexpression of NFkappaB. Although two binding sites for NFkappaB were identified within the G6Pase promoter, neither of these sites, nor the insulin response unit or binding sites for Sp proteins, was necessary for the regulation of G6Pase promoter activity by TNFalpha. In conclusion, the data indicate that the activation of NFkappaB is sufficient to suppress G6Pase gene expression, and is required for the regulation by TNFalpha, but not by insulin. We propose that NFkappaB does not act by binding directly to the G6Pase promoter.
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PMID:Tumour necrosis factor alpha decreases glucose-6-phosphatase gene expression by activation of nuclear factor kappaB. 1516 11

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

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


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