Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Insulin regulates the rate of expression of many hepatic genes, including PEPCK, glucose-6-phosphatase (G6Pase), and glucose-6-phosphate dehydrogenase (G6PDHase). The expression of these genes is also abnormally regulated in type 2 diabetes. We demonstrate here that treatment of hepatoma cells with 5-aminoimidazole-4-carboxamide riboside (AICAR), an agent that activates AMP-activated protein kinase (AMPK), mimics the ability of insulin to repress PEPCK gene transcription. It also partially represses G6Pase gene transcription and yet has no effect on the expression of G6PDHase or the constitutively expressed genes cyclophilin or beta-actin. Several lines of evidence suggest that the insulin-mimetic effects of AICAR are mediated by activation of AMPK. Also, insulin does not activate AMPK in H4IIE cells, suggesting that this protein kinase does not link the insulin receptor to the PEPCK and G6Pase gene promoters. Instead, AMPK and insulin may lie on distinct pathways that converge at a point upstream of these 2 gene promoters. Investigation of the pathway by which AMPK acts may therefore give insight into the mechanism of action of insulin. Our results also suggest that activation of AMPK would inhibit hepatic gluconeogenesis in an insulin-independent manner and thus help to reverse the hyperglycemia associated with type 2 diabetes.
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PMID:5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. 1086 40

Expression of the catalytic subunit of glucose-6-phosphatase (G6Pase) has recently been shown to be transactivated by the transcription factor FKHR. Insulin and conditions of energy depletion are known repressors of the G6Pase gene. Whereas insulin is known to inhibit G6Pase expression by phosphorylation and nuclear exclusion of FKHR, the mechanism of repression of G6Pase by energy depletion is unknown. Here, we have studied the effect of glucose starvation and AICAR, an activator of AMP-activated protein kinase (AMPK) on G6Pase expression and the expressional level of FKHR-protein in hepatic cells. Using a H4-hepatoma cell line stably overexpressing FKHR, we found that both glucose starvation and treatment of cells with AICAR strongly repressed G6Pase expression and led to an almost complete disappearance of the FKHR protein, whereas the levels of control proteins and FKHR mRNA were not affected. Our data suggest that AICAR and glucose starvation inhibit G6Pase expression by a reduction of the cellular level of FKHR, presumably mediated by specific degradation of the protein.
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PMID:Regulation of the forkhead transcription factor FKHR (FOXO1a) by glucose starvation and AICAR, an activator of AMP-activated protein kinase. 1213 May 86

Acetic acid (AcOH), which is a short-chain fatty acid, is reported to have some beneficial effects on metabolism. To test the hypothesis that feeding of AcOH exerts beneficial effects on glucose homeostasis in type 2 diabetes, we fed either a standard diet or one containing 0.3% AcOH to KK-A(y) mice for 8 weeks. Fasting plasma glucose and HbA1c levels were lower in mice fed AcOH for 8 weeks than in control mice. AcOH also reduced the expression of genes involved in gluconeogenesis and lipogenesis, which is in part regulated by 5'-AMP-activated protein kinase (AMPK) in the liver. Finally, sodium acetate, in the form of neutralized AcOH, directly activated AMPK and lowered the expression of genes such as for glucose-6-phosphatase and sterol regulatory element binding protein-1 in rat hepatocytes. These results indicate that the hypoglycemic effect of AcOH might be due to activation of AMPK in the liver.
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PMID:Acetic acid activates hepatic AMPK and reduces hyperglycemia in diabetic KK-A(y) mice. 1663 May 52

Fructose-2,6-bisphosphate (F26P2) was identified as a regulator of glucose metabolism over 25 years ago. A truly bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PFK2/FBP2), with two active sites synthesizes F26P2 from fructose-6-phosphate (F6P) and ATP or degrades F26P2 to F6P and Pi. In the classic view, F26P2 regulates glucose metabolism by allosteric effects on 6-phosphofructo-1-kinase (6PFK1, activation) and fructose-1,6-bisphosphatase (FBPase, inhibition). When levels of F26P2 are high, glycolysis is enhanced and gluconeogenesis is inhibited. In this regard, altering levels of F26P2 via 6PFK2/FBP2 overexpression has been used for metabolic modulation, and has been shown capable of restoring euglycemia in rodent models of diabetes. Recently, a number of novel observations have suggested that F26P2 has much broader effects on the enzymes of glucose metabolism. This is evidenced by the effects of F26P2 on the gene expression of two key glucose metabolic enzymes, glucokinase (GK) and glucose-6-phosphatase (G6Pase). When levels of F26P2 are elevated in the liver, the gene expression and protein amount of GK is increased whereas G6Pase is decreased. These coordinated changes in GK and G6Pase protein illustrate how F26P2 regulates glucose metabolism. F26P2 also affects the gene expression of enzymes related to lipid metabolism. When F26P2 levels are elevated in liver, the expression of two key lipogenic enzymes, acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) is reduced, contributing to a unique coordinated decrease in lipogenesis. When combined, F26P2 effects on glucose and lipid metabolism provide cooperative regulation of fuel metabolism. The regulatory roles for F26P2 have also expanded to transcription factors, as well as certain key proteins (enzymes) of signaling and/or energy sensoring. Although some effects may be secondary to changes in metabolite levels, high levels of F26P2 have been shown to regulate protein amount and/or phosphorylation state of hepatic nuclear factor 1-alpha (HNF1alpha), carbohydrate response element binding protein (ChREBP), peroxisome proliferators-activated receptor alpha (PPARalpha), and peroxisome proliferators-activated receptor gamma co-activator 1beta (PGC1beta), as well as Akt and AMP-activated protein kinase (AMPK). Importantly, changes in these transcription factors, signaling proteins, and sensor proteins are produced in a way that appropriately coordinates whole body fuel metabolism.
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PMID:Roles for fructose-2,6-bisphosphate in the control of fuel metabolism: beyond its allosteric effects on glycolytic and gluconeogenic enzymes. 1686 Mar 76

Sodium arsenite has been demonstrated to alter the expression of genes associated with glucose homeostasis in tissues involved in the pathogenesis of type 2 diabetes; however, the underlying molecular mechanism has not been fully elucidated yet. In this study, we report that the sodium arsenite-induced gene expression of the small heterodimer partner (SHP; NR0B2), an atypical orphan nuclear receptor, regulates the expression of hepatic gluconeogenic genes. Sodium arsenite augments hepatic SHP mRNA levels in an AMP-activated protein kinase (AMPK)-dependent manner. Sodium arsenite activated AMPK and was shown to perturb cellular ATP levels. The arsenite-induced SHP mRNA level was blocked by adenoviral overexpression of dominant negative AMPK (Ad-dnAMPKalpha) or by the AMPK inhibitor compound C in hepatic cell lines. We demonstrated the dose-dependent induction of SHP mRNA levels by sodium arsenite and repressed the forskolin/dexamethasone-induced gene expression of the key hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Ad-dnAMPKalpha blocked the repressive effects of arsenite-induced SHP on PEPCK and G6Pase. Sodium arsenite inhibited the promoter activity of PEPCK and G6Pase, and this repression was abolished by small interfering (si)RNA SHP treatments. The knockdown of SHP expression by oligonucleotide siRNA SHP or adenoviral siRNA SHP released the sodium arsenite-mediated repression of forskolin/dexamethasone-stimulated PEPCK and G6Pase gene expression in a variety of hepatic cell lines. Results from our study suggest that sodium arsenite induces SHP via AMPK to inhibit the expression of hepatic gluconeogenic genes and also provide us with a novel molecular mechanism of arsenite-mediated regulation of hepatic glucose homeostasis.
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PMID:Sodium arsenite induces orphan nuclear receptor SHP gene expression via AMP-activated protein kinase to inhibit gluconeogenic enzyme gene expression. 1850 31

In order to observe the effect of increased serum resistin on glucose metabolism, insulin sensitivity, and hepatic insulin resistance (IR), mice were intravenously injected with recombinant adenovirus carrying the resistin gene (Adv-resistin-EGFP). Changes in hepatic glucose metabolism were observed using the Periodic Acid-Schiff method. Hepatic AMP-activated protein kinase (AMPK) activation was assessed by Western blot analysis, and glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was determined using real-time RT-PCR. Although no effect on fasting blood glucose was detected, increased fasting insulin levels, decreased glucose tolerance and insulin sensitivity, and reduced hepatic glycogen levels and AMPK activation were seen in the Adv-resistin-EGFP mice. Finally, elevated G6Pase and PEPCK mRNA expression levels were detected upon overexpression of resistin. Resistin may inhibit hepatic AMPK activity, which results in elevated expression of gluconeogenic enzymes thereby affecting glucose metabolism and leading to decreased glycogen storage that contributes to the development of hepatic IR.
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PMID:Effects of resistin expression on glucose metabolism and hepatic insulin resistance. 1918 34

Resistin is a 12.5-KDa cysteine-rich peptide that has been implicated in the impairment of glucose homeostasis via the AMP-activated protein kinase (AMPK) pathway in a rodent model. However, the role resistin plays in humans is controversial. This study investigated the effect of resistin on glucose metabolism and insulin signaling using human recombinant resistin and small interfering RNA (siRNA) against AMPKalpha2 to treat the human liver HepG2 cells. The mRNA of key genes involved in glucose metabolism and the insulin-signaling pathway were detected by real-time RT-PCR. Phosphorylation levels of Akt and AMPK were measured by western blot. The incorporation of D-[U-(14)C] glucose into glycogen was quantitated by liquid scintillation counting. The results demonstrate that resistin stimulated expressions of glucose-6-phosphatase (G6Pase), phosphoenolypyruvate carboxykinase (PEPCK), and suppressor of cytokine signaling 3 (SOCS-3), repressed the expressions of insulin receptor substrate 2(IRS-2) and glucose transporter 2(GLUT2). In addition, resistin inhibited the insulin-induced phosphorylation of Akt independent of AMPK. In conclusion, our findings suggest that resistin induces insulin resistance in HepG2 cells at least partly via induction of SOCS-3 expression and reduction of Akt phosphorylation through an AMPK-independent mechanism. Resistin also increases glucose production via AMPK-mediated upregulated expression of the genes encoding hepatic gluconeogenic enzymes, G6Pase, and PEPCK.
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PMID:Resistin induces insulin resistance by both AMPK-dependent and AMPK-independent mechanisms in HepG2 cells. 1944 Aug 59

The biguanide derivative metformin is a potent anti-diabetic drug widely used in the treatment of type 2 diabetes mellitus. Its major effect on glucose metabolism consists in the inhibition of hepatic glucose production. Since the mechanisms of metformin action are only partially understood at the molecular level, we studied the regulation of the gene promoter activity of glucose-6-phosphatase (G6Pase), the central hepatic gluconeogenic enzyme, by this drug. We have found that both metformin and insulin inhibit the basal and dexamethasone/cAMP-stimulated G6Pase promoter activity in hepatoma cells. Since one of the pharmacological targets of metformin is AMP-activated protein kinase (AMPK) and activation of AMPK is known to inhibit hepatic glucose production by the suppression of G6Pase gene transcription, we studied the effect of AMPK in this context. Under nonstimulated conditions, the inhibitory effect of both insulin and metformin was partially counteracted to a similar extent by treatment with compound C, a specific inhibitor of AMPK. In contrast, under conditions of stimulation with dexamethasone and cAMP, treatment with compound C reversed the inhibitory effect of metformin on G6Pase promoter activity to a similar extent as compared to nonstimulated conditions, whereas the effect of insulin was almost resistant to treatment with the AMPK-antagonist. These data indicate a differential AMPK-dependent regulation of G6Pase gene expression by insulin and metformin under basal and dexamethasone/cAMP-stimulated conditions.
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PMID:Regulation of glucose-6-phosphatase gene expression by insulin and metformin. 1957 80

Metformin is widely used as a hypoglycemic agent for the treatment of type 2 diabetes. Both metformin and rotenone, an inhibitor of respiratory chain complex I, suppressed glucose-6-phosphatase (G6pc), a rate limiting enzyme of liver glucose production, mRNA expression in a rat hepatoma cell line accompanied by a reduction of intracellular ATP concentration and an activation of AMP-activated protein kinase (AMPK). When yeast NADH-quinone oxidoreductase 1 (NDI1) gene was introduced into the cells, neither inhibition of ATP synthesis nor activation of AMPK was induced by these agents. Interestingly, in contrast to rotenone treatment, G6pc mRNA down-regulation was observed in the NDI1 expressing cells after metformin treatment. Since NDI1 can functionally complement the complex I under the presence of metformin or rotenone, our results indicate that metformin induces down-regulation of G6pc expression through an inhibition of complex I and an activation of AMPK-independent mechanism.
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PMID:Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism. 1966 96

Hepatic gluconeogenesis is tightly balanced by opposing stimulatory (glucagon) and inhibitory (insulin) signaling pathways. Hepatocyte growth factor (HGF) is a pleiotropic growth factor that mediates diverse biological processes. In this study, we investigated the effect of HGF and its family member, macrophage-stimulating factor (MSP), on hepatic gluconeogenesis in primary hepatocytes. HGF and MSP significantly repressed expression of the key hepatic gluconeogenic enzyme genes, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (Glc-6-Pase) and reduced glucose production. HGF and MSP activated small heterodimer partner (SHP) gene promoter and induced SHP mRNA and protein levels, and the effect of HGF and MSP on SHP gene expression was demonstrated to be mediated via activation of the AMP-activated protein kinase (AMPK) signaling pathway. We demonstrated that upstream stimulatory factor-1 (USF-1) specifically mediated HGF effect on SHP gene expression, and inhibition of USF-1 by dominant negative USF-1 significantly abrogated HGF-mediated activation of the SHP promoter. Elucidation of the mechanism showed that USF-1 bound to E-box-1 in the SHP promoter, and HGF increased USF-1 DNA binding on the SHP promoter via AMPK and DNA-dependent protein kinase-mediated pathways. Adenoviral overexpression of USF-1 significantly repressed PEPCK and Glc-6-Pase gene expression and reduced glucose production. Knockdown of endogenous SHP expression significantly reversed this effect. Finally, knockdown of SHP or inhibition of AMPK signaling reversed the ability of HGF to suppress hepatocyte nuclear factor 4alpha-mediated up-regulation of PEPCK and Glc-6-Pase gene expression along with the HGF- and MSP-mediated suppression of gluconeogenesis. Overall, our results suggest a novel signaling pathway through HGF/AMPK/USF-1/SHP to inhibit hepatic gluconeogenesis.
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PMID:Hepatocyte growth factor family negatively regulates hepatic gluconeogenesis via induction of orphan nuclear receptor small heterodimer partner in primary hepatocytes. 1972 Aug 31


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