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)

The mechanisms responsible for the antidiabetic activity of both the white ginseng radix (Ginseng Radix Alba, GRA) and the rootlet (Ginseng Radix Palva, GRP) were investigated. After a four week oral administration, the fasting blood glucose levels in the GRA- and GRP-treated groups were lower when compared to the control group. To elucidate the hypoglycemic mechanism(s) of the ginseng radices, glucose absorption from the small intestine, hepatic hexokinase and glucose-6-phosphatase activities, in addition to PPAR-gamma expression in adipose tissue were examined. The results strongly suggest that GRA can improve hyperglycemia in KKAy mice, possibly by blocking intestinal glucose absorption and inhibiting hepatic glucose-6-phosphatase, and GRP through the upregulation of adipocytic PPAR-y protein expression as well as inhibiting intestinal glucose absorption.
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PMID:Comparisons between white ginseng radix and rootlet for antidiabetic activity and mechanism in KKAy mice. 1144 80

In models of type 2 diabetes the expression of beta-cell genes is altered, but these changes have not fully explained the impairment in beta-cell function. We hypothesized that changes in beta-cell phenotype and global alterations in both carbohydrate and lipid pathways are likely to contribute to secretory abnormalities. Therefore, expression of genes involved in carbohydrate and lipid metabolism were analyzed in islets 4 weeks after 85-95% partial pancreatectomy (Px) when beta-cells have impaired glucose-induced insulin secretion and ATP synthesis. Px rats after 1 week developed mild to severe hyperglycemia that was stable for the next 3 weeks, whereas neither plasma triglyceride, non-esterified fatty acid, or islet triglyceride levels were altered. Expression of peroxisome proliferator-activated receptors (PPARs), with several target genes, were reciprocally regulated; PPARalpha was markedly reduced even at low level hyperglycemia, whereas PPARgamma was progressively increased with increasing hyperglycemia. Uncoupling protein 2 (UCP-2) was increased as were other genes barely expressed in sham islets including lactate dehydrogenase-A (LDH-A), lactate (monocarboxylate) transporters, glucose-6-phosphatase, fructose-1,6-bisphosphatase, 12-lipoxygenase, and cyclooxygenase 2. On the other hand, the expression of beta-cell-associated genes, insulin, and GLUT2 were decreased. Treating Px rats with phlorizin normalized hyperglycemia without effecting plasma fatty acids and reversed the changes in gene expression implicating the importance of hyperglycemia per se in the loss of beta-cell phenotype. In addition, parallel changes were observed in beta-cell-enriched tissue dissected by laser capture microdissection from the central core of islets. In conclusion, chronic hyperglycemia leads to a critical loss of beta-cell differentiation with altered expression of genes involved in multiple metabolic pathways diversionary to normal beta-cell glucose metabolism. This global maladaptation in gene expression at the time of increased secretory demand may contribute to the beta-cell dysfunction found in diabetes.
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PMID:Genetic regulation of metabolic pathways in beta-cells disrupted by hyperglycemia. 1178 87

It has recently been shown that adenoviral-mediated expression of peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1 alpha) in hepatocytes stimulates glucose-6-phosphatase catalytic subunit (G6Pase) gene expression. A combination of fusion gene, gel retardation and chromatin immunoprecipitation assays revealed that, in H4IIE cells, PGC-1 alpha mediates this stimulation through an evolutionarily conserved region of the G6Pase promoter that binds hepatocyte nuclear factor-4 alpha.
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PMID:Hepatocyte nuclear factor-4 alpha mediates the stimulatory effect of peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1 alpha) on glucose-6-phosphatase catalytic subunit gene transcription in H4IIE cells. 1241 93

The liver plays several critical roles in the metabolic adaptation to fasting. We have shown previously that the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is induced in fasted or diabetic liver and activates the entire program of gluconeogenesis. PGC-1alpha interacts with several nuclear receptors known to bind gluconeogenic promoters including the glucocorticoid receptor, hepatocyte nuclear factor 4alpha (HNF4alpha), and the peroxisome proliferator-activated receptors. However, the genetic requirement for any of these interactions has not been determined. Using hepatocytes from mice lacking HNF4alpha in the liver, we show here that PGC-1alpha completely loses its ability to activate key genes of gluconeogenesis such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase when HNF4alpha is absent. It is also shown that PGC-1alpha can induce genes of beta-oxidation and ketogenesis in hepatocytes, but these effects do not require HNF4alpha. Analysis of the glucose-6-phosphatase promoter indicates a key role for HNF4alpha-binding sites that function robustly only when HNF4alpha is coactivated by PGC-1alpha. These data illustrate the involvement of PGC-1alpha in several aspects of the hepatic fasting response and show that HNF4alpha is a critical component of PGC-1alpha-mediated gluconeogenesis.
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PMID:Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. 1265 43

The control of lipid and glucose metabolism is closely linked. The nuclear receptors liver X receptor (LXR)alpha and LXR beta have been implicated in gene expression linked to lipid homeostasis; however, their role in glucose metabolism is not clear. We demonstrate here that the synthetic LXR agonist GW3965 improves glucose tolerance in a murine model of diet-induced obesity and insulin resistance. Analysis of gene expression in LXR agonist-treated mice reveals coordinate regulation of genes involved in glucose metabolism in liver and adipose tissue. In the liver, activation of LXR led to the suppression of the gluconeogenic program including down-regulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase expression. Inhibition of gluconeogenic genes was accompanied by an induction in expression of glucokinase, which promotes hepatic glucose utilization. In adipose tissue, activation of LXR led to the transcriptional induction of the insulin-sensitive glucose transporter, GLUT4. We show that the GLUT4 promoter is a direct transcriptional target for the LXR/retinoid X receptor heterodimer and that the ability of LXR ligands to induce GLUT4 expression is abolished in LXR null cells and animals. Consistent with their effects on GLUT4 expression, LXR agonists promote glucose uptake in 3T3-L1 adipocytes in vitro. Thus, activation of LXR alters the expression of genes in liver and adipose tissue that collectively would be expected to limit hepatic glucose output and improve peripheral glucose uptake. These results outline a role for LXRs in the coordination of lipid and glucose metabolism.
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PMID:Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. 1269 4

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

Hepatic gluconeogenesis is essential for maintaining blood glucose levels during fasting and is the major contributor to postprandial and fasting hyperglycemia in diabetes. Gluconeogenesis is a classic cAMP/protein kinase A-dependent process initiated by glucagon, which is elevated in the blood during fasting and in diabetes. In this study, we have shown that p38 mitogen-activated protein kinase (p38) was activated in liver by fasting and in primary hepatocytes by glucagon or forskolin. Fasting plasma glucose levels were reduced upon blockade of p38 with either a chemical inhibitor or small interference RNA in mice. In examining the mechanism, inhibition of p38 suppressed gluconeogenesis in liver, along with expression of key gluconeogenic genes, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Peroxisome proliferator-activated receptor gamma coactivator 1alpha and cAMP-response element-binding protein have been shown to be important mediators of hepatic gluconeogenesis. We have shown that inhibition of p38 prevented transcription of the PPARgamma coactivator 1alpha gene as well as phosphorylation of cAMP-response element-binding protein. Together, our results from in vitro and in vivo studies define a model in which cAMP-dependent activation of genes involved in gluconeogenesis is dependent upon the p38 pathway, thus adding a new player to our evolving understanding of this physiology.
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PMID:p38 Mitogen-activated protein kinase plays a stimulatory role in hepatic gluconeogenesis. 1627 51

Flavonoids have been identified as the antidiabetic components in a number of traditional ethnic remedies. However, the mechanisms whereby these compounds exert their hypoglycemic and hypolipidemic action in type-2 diabetes have rarely been investigated. Therefore, this study investigated the effect of the flavonoids hesperidin and naringin on glucose and lipid regulation in C57BL/KsJ-db/db mice. Hesperidin and naringin both significantly increased the glucokinase mRNA level, while naringin also lowered the mRNA expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver. In addition, the hepatic glucose transporter 2 protein expression was significantly reduced, while the expression of adipocyte glucose transporter 4 and hepatic and adipocyte peroxisome proliferator-activated receptor gamma were elevated in the hesperidin and naringin groups when compared with the control group. Furthermore, hesperidin and naringin effectively lowered the plasma free fatty acid and plasma and hepatic triglyceride levels, and simultaneously reduced the hepatic fatty acid oxidation and carnitine palmitoyl transferase activity. These changes were seemingly attributable to a suppression of the hepatic fatty acid synthase, glucose-6-phosphate dehydrogenase, and phosphatidate phosphohydrolase activities and an increase in the fecal triglycerides. The two flavonoids also led to a decrease in the plasma and hepatic cholesterol levels that may have been partly due to the decreased hepatic 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase and acyl CoA: cholesterol acyltransferase (ACAT) activities and increased fecal cholesterol. Consequently, the current results suggest that hesperidin and naringin are beneficial for improving hyperlipidemia and hyperglycemia in type-2 diabetic animals by partly regulating the fatty acid and cholesterol metabolism and affecting the gene expression of glucose-regulating enzymes.
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PMID:Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. 1642 99

Free fatty acids (FFA) are considered as a causative link between obesity and diabetes. In various animal models and in humans FFA can stimulate hepatic gluconeogenesis. Although the in vivo role of FFA in hepatic gluconeogenesis has been clearly established, the intracellular role of FFA and related signaling pathway remain unclear in the regulation of hepatic gluconeogenic gene transcription. In this study, we have identified p38 mitogen-activated protein kinase (p38) as a critical signaling component in FFA-induced transcription of key gluconeogenic genes. We show in primary hepatocytes that both mid- and long-chain fatty acids (saturated or unsaturated) could activate p38 and increase levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase, and peroxisome proliferator-activated receptor gamma coactivator alpha (PGC-1alpha) gene transcripts. The FFA-induced expression of PEPCK and PGC-1alpha genes and gluconeogenesis in isolated hepatocytes could be blocked by the inhibition of p38. Furthermore, PGC-1alpha phosphorylation by p38 was necessary for FFA-induced activation of the PEPCK promoter. Additionally, FFA stimulated phosphorylation of cAMP-response element-binding protein (CREB) through p38. The overexpression of the dominant-negative CREB prevented FFA-induced activation of the PEPCK promoter. Finally, we show that FFA activation of p38 requires protein kinase Cdelta. Together, our results indicate that p38 plays a critical role in FFA-induced transcription of gluconeogenic genes, and the known gluconeogenic regulators, PGC-1alpha and CREB, are also integral parts of FFA-stimulated transcription of gluconeogenic genes.
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PMID:p38 Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes. 1680 82

Resistin is a 12.5-kDa cysteine-rich protein secreted from adipose tissue and is an important factor linking obesity with insulin resistance. Here, we investigated the effect of resistin on glucose tolerance in adult human hepatocytes (L-02 cells). In this study, resistin cDNA was transfected into L-02 cells, and glucose concentration and glucokinase activity were determined subsequently. The data indicated resistin impaired, insulin-stimulated glucose utilization, which implied liver was a target tissue of resistin. To understand its molecular mechanism, mRNA levels of key genes in glucose metabolism and insulin signaling pathway were analyzed. The results demonstrated resistin-stimulated expression of glucose-6-phosphatase (G6Pase), sterol regulatory element-binding protein 1c (SREBP1c) and suppressor of cytokine signaling 3 (SOCS-3), repressed expression of peroxisome proliferator-activated receptor gamma (PPARgamma) as well as insulin receptor substrate 2 (IRS-2). Given that glucokinase (GK) activity and glucose transporter 2 (GLUT2) expression were not altered, we presumed that resistin did not effect them. Moreover, resistin lowered mRNA levels of IRS-2 while stimulating SOCS-3 expression, which suggests it impairs glucose tolerance by blocking the insulin signal transduction pathway.
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PMID:Resistin overexpression impaired glucose tolerance in hepatocytes. 1719 39


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