Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.1.1.32 (phosphoenolpyruvate carboxykinase)
 4,204 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several hormones, including insulin, glucagon, and glucocorticoids, regulate the expression of the rate-limiting gluconeogenic enzyme, phosphoenolpyruvate carboxykinase [GTP: oxaloacetate carboxy-lyase (transphosphorylating); EC 4.1.1.32; PEPCK] in liver. In this report we demonstrate that retinoic acid (RA) also regulates PEPCK expression by inducing a 3-fold increase in the rate of transcription of the PEPCK gene. A RA response element located between -468 and -431 in the PEPCK promoter mediates a 7-fold increase in expression of a chimeric construct containing the basal PEPCK promoter ligated to the chloramphenicol acetyltransferase reporter gene. This element confers RA responsiveness through the heterologous thymidine kinase promoter and functions relatively independent of position and orientation. An 18-base-pair core sequence (-451 to -434) (i) mediates an effect of RA on PEPCK gene expression and contains motifs found in two other RA response elements; (ii) corresponds to AF1, an accessory factor element that is an integral component of the complex glucocorticoid response unit in the PEPCK gene promoter; (iii) is in a region involved in the developmental expression of the PEPCK gene; and (iv) shows homology to elements involved in the tissue-specific regulation of genes, including the hepatic apolipoprotein genes and the alpha 1-antitrypsin gene.
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PMID:A retinoic acid response element is part of a pleiotropic domain in the phosphoenolpyruvate carboxykinase gene. 184 96

As part of an ongoing search for diabetes susceptibility loci, we tested linkage with non-insulin-dependent diabetes mellitus (NIDDM) for 19 candidate loci or regions chosen for their potential to affect directly or indirectly the action of insulin. Loci were associated with insulin resistance, known effects on lipid metabolism, or effects on glucose metabolism or insulin action. Loci included the insulin-responsive (GLUT4) glucose transporter, hexokinase 2, glucagon, growth hormone, insulin receptor substrate 1 (IRS1), phosphoenolpyruvate carboxykinase, hepatic and muscle forms of pyruvate kinase, hepatic phosphofructokinase, the apolipoprotein B and the apolipoprotein A2 cluster, lipoprotein lipase, hepatic triglyceride lipase, the very-low-density-lipoprotein receptor, and the Pima insulin resistance locus on chromosome 4. For several candidates, no specific informative marker was available; consequently, we tested the surrounding region with highly informative markers. These regions included the diabetes-associated ras-like gene, rad, and the cholesterol ester-transfer gene, both mapped to chromosome 16. Additionally, we tested for linkage with markers at the tumor necrosis factor-alpha gene and the Friedreich's ataxia region. All regions were tested for linkage with microsatellite polymorphisms in > 450 individuals from a minimum of 16 Caucasian families under parametric (LINKAGE 5.1) and nonparametric (affected pedigree member) models.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Linkage analysis of 19 candidate regions for insulin resistance in familial NIDDM. 758 21

Insulin regulates the expression of multiple hepatic genes through a conserved insulin response sequence (IRS) (CAAAAC/TAA) by an as yet undetermined mechanism. Protein kinase B/Akt (PKB/Akt), a member of the PKA/PKC serine/threonine kinase family, functions downstream from phosphatidylinositol 3'-kinase (PI3K) in mediating effects of insulin on glucose transport and glycogen synthesis. We asked whether PKB/Akt mediates sequence-specific effects of insulin on hepatic gene expression using the model of the insulin-like growth factor binding protein-1 (IGFBP-1) promoter. Insulin lowers IGFBP-1 mRNA levels, inhibits IGFBP-1 promoter activity, and activates PKB/Akt in HepG2 hepatoma cells through a PI3K-dependent, rapamycin-insensitive mechanism. Constitutively active PI3K and PKB/Akt are each sufficient to mediate effects of insulin on the IGFBP-1 promoter in a nonadditive fashion. Dominant negative K179 PKB/Akt disrupts the ability of insulin and PI3K to activate PKB/Akt and to inhibit promoter activity. The IGFBP-1 promoter contains two IRSs each of which is sufficient to mediate sequence-specific effects of insulin, PI3K, and PKB/Akt on promoter activity. Highly related IRSs from the phosphoenolpyruvate carboxykinase and apolipoprotein CIII genes also are effective in this setting. These results indicate that PKB/Akt functions downstream from PI3K in mediating sequence-specific effects of insulin on the expression of IGFBP-1 and perhaps multiple hepatic genes through a conserved IRS.
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PMID:Protein kinase B/Akt mediates effects of insulin on hepatic insulin-like growth factor-binding protein-1 gene expression through a conserved insulin response sequence. 949 82

The expression of the peroxisome proliferator-activated receptor-alpha (PPARalpha) as well as of some related genes was studied in rat liver at different stages of development (from 19-day-old fetuses to 1 month-old rats). The level of PPARalpha mRNA appeared higher in neonates than in fetuses or 1 month-old rats. Whereas the pattern for phosphoenolpyruvate carboxykinase (PEPCK) mRNA level was similar to that of PPARalpha, the mRNA level of both acyl-CoA oxidase (ACO) and apolipoprotein CIII (apo CIII) showed diverse profiles. Western blotting analysis also revealed an increased level of PPARalpha protein in liver of suckling rats. Similarities of mRNA PEPCK and PPARalpha expression indicate a common control mechanism, where both nutritional and hormonal factors may be involved.
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PMID:Peroxisome proliferator-activated receptor-alpha expression in rat liver during postnatal development. 1101 88

We studied the effect of pioglitazone on the transcription of 42 genes associated with diabetes to examine the relationship between the antidiabetic action of thiazolidinediones (TZDs) and their ability to modulate transcription through their peroxisome proliferater-activated receptor (PPAR)-agonistic activity. Diabetic (db/db) mice were orally administered with pioglitazone for two weeks. Total RNA was prepared from liver, muscle and adipocytes and the quantity of mRNA was determined by comparative RT-PCR. The expression of diabetes-related genes was compared between lean and untreated db/db mice and between untreated and drug-treated db/db mice. The onset of diabetes was associated with a considerable alteration in the expression of a large number of diabetes-related genes. Treatment of db/db mice with pioglitazone modulated the expression of genes involved in the metabolism of glucose, lipids and lipoproteins. This included genes for phosphoenolpyruvate carboxykinase, beta-oxidation enzymes, lipoprotein lipase, apolipoprotein AI and uncoupling proteins. Most of the genes responsible for insulin signaling were unaffected. Administration of pioglitazone was also shown to induce PPARgamma expression in liver and muscle. It is therefore possible to hypothesize that TZDs may ameliorate diabetes through a mechanism of action involving a direct decrease in plasma glucose and triglyceride levels and improvements in free fatty acid-induced insulin resistance.
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PMID:Alteration in expression profiles of a series of diabetes-related genes in db/db mice following treatment with thiazolidinediones. 1112 33

The adipocyte-derived hormone resistin has been proposed as a possible link between obesity and insulin resistance in murine models. Many recent studies have reported physiological roles for resistin in glucose homeostasis, one of which is enhancement of glucose production from the liver by up-regulating gluconeogenic enzymes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. However, its in vivo roles in lipid metabolism still remain to be clarified. In this study, we investigated the effects of resistin overexpression on insulin action and lipid metabolism in C57BL/6 mice using an adenoviral gene transfer technique. Elevated plasma resistin levels in mice treated with the resistin adenovirus (AdmRes) were confirmed by Western blotting analysis and RIAs. Fasting plasma glucose levels did not differ between AdmRes-treated mice and controls, but the basal insulin concentration was significantly elevated in AdmRes-treated mice. In AdmRes-treated mice, the glucose-lowering effect of insulin was impaired, as evaluated by insulin tolerance tests. Furthermore, total cholesterol and triglyceride concentrations were significantly higher, whereas the high-density lipoprotein cholesterol level was significantly lower. Lipoprotein analysis revealed that low-density lipoprotein was markedly increased in AdmRes-treated mice, compared with controls. In addition, in vivo Triton WR-1339 studies showed evidence of enhanced very low-density lipoprotein production in AdmRes-treated mice. The expressions of genes involved in lipoprotein metabolism, such as low-density lipoprotein receptor and apolipoprotein AI in the liver, were decreased. These results suggest that resistin overexpression induces dyslipidemia in mice, which is commonly seen in the insulin-resistant state, partially through enhanced secretion of lipoproteins.
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PMID:Adenovirus-mediated high expression of resistin causes dyslipidemia in mice. 1547 67

Posttransplantation diabetes mellitus (PTDM) is a frequent complication in immunosuppressive therapy. To better understand the molecular events associated with PTDM we investigated the effect of cyclosporine on expression and activity of hepatic nuclear factor (HNF)1alpha and 4alpha and on genes coding for glucose metabolism in cultures of the rat insulinoma cell line INS-1E, the human epithelial cell line Caco-2 and with Zucker diabetic fatty (ZDF) rats. In the pancreas of untreated but diabetic animals expression of HNF4alpha, insulin1, insulin2 and of phosphoenolpyruvate carboxykinase was significantly repressed. Furthermore, cyclosporine treatment of the insulinoma-1E cell line resulted in remarkable reduction in HNF4alpha protein and INS1 as well as INS2 gene expression, while transcript expression of HNF4alpha, apolipoprotein C2, glycerolkinase, pyruvatekinase and aldolase B was repressed in treated Caco-2 cells. Furthermore, with nuclear extracts of cyclosporine treated cell lines protein expression and DNA binding activity of hepatic nuclear factors was significantly repressed. As cyclosporine inhibits the calcineurin dependent dephosphorylation of nuclear factor of activated T-cells (NFAT) we also searched for binding sites for NFAT in the pancreas specific P2 promoter of HNF4alpha. Notably, we observed repressed NFAT binding to a novel DNA binding site in the P2 promoter of HNF4alpha. Thus, cyclosporine caused inhibition of DNA binding of two important regulators for insulin signaling, i.e. NFAT and HNF4alpha. We further investigated HNF4alpha transcript expression and observed >200-fold differences in abundance in n = 14 patients. Such variability in expression might help to identify individuals at risk for developing PTDM. We propose cyclosporine to repress HNF4alpha gene and protein expression, DNA-binding to targeted promoters and subsequent regulation of genes coding for glucose metabolism and of pancreatic beta-cell function.
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PMID:HNF4alpha and HNF1alpha dysfunction as a molecular rational for cyclosporine induced posttransplantation diabetes mellitus. 1925 40