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:4.1.1.49 (phosphoenolpyruvate carboxykinase)
4,654 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoids (GCs) increase hepatic gluconeogenesis and play an important role in the regulation of hepatic glucose output. Whereas systemic GC inhibition can alleviate hyperglycemia in rodents and humans, it results in adrenal insufficiency and stimulation of the hypothalamic-pituitary-adrenal axis. In the present study, we used optimized antisense oligonucleotides (ASOs) to cause selective reduction of the glucocorticoid receptor (GCCR) in liver and white adipose tissue (WAT) and evaluated the resultant changes in glucose and lipid metabolism in several rodent models of diabetes. Treatment of ob/ob mice with GCCR ASOs for 4 weeks resulted in approximately 75 and approximately 40% reduction in GCCR mRNA expression in liver and WAT, respectively. This was accompanied by approximately 65% decrease in fed and approximately 30% decrease in fasted glucose levels, a 60% decrease in plasma insulin concentration, and approximately 20 and 35% decrease in plasma resistin and tumor necrosis factor-alpha levels, respectively. Furthermore, GCCR ASO reduced hepatic glucose production and inhibited hepatic gluconeogenesis in liver slices from basal and dexamethasone-treated animals. In db/db mice, a similar reduction in GCCR expression caused approximately 40% decrease in fed and fasted glucose levels and approximately 50% reduction in plasma triglycerides. In ZDF and high-fat diet-fed streptozotocin-treated (HFD-STZ) rats, GCCR ASO treatment caused approximately 60% reduction in GCCR expression in the liver and WAT, which was accompanied by a 40-70% decrease in fasted glucose levels and a robust reduction in plasma triglyceride, cholesterol, and free fatty acids. No change in circulating corticosterone levels was seen in any model after GCCR ASO treatment. To further demonstrate that GCCR ASO does not cause systemic GC antagonism, normal Sprague-Dawley rats were challenged with dexamethasone after treating with GCCR ASO. Dexamethasone increased the expression of GC-responsive genes such as PEPCK in the liver and decreased circulating lymphocytes. GCCR ASO treatment completely inhibited the increase in dexamethasone-induced PEPCK expression in the liver without causing any change in the dexamethasone-induced lymphopenia. These studies demonstrate that tissue-selective GCCR antagonism with ASOs may be a viable therapeutic strategy for the treatment of the metabolic syndrome.
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PMID:Reduction of hepatic and adipose tissue glucocorticoid receptor expression with antisense oligonucleotides improves hyperglycemia and hyperlipidemia in diabetic rodents without causing systemic glucocorticoid antagonism. 1591 8

Abstract Specific blockade of glucocorticoid receptor (GCCR) action in the liver without affecting the hypothalamus-pituitary-adrenal axis could be a novel pharmaceutical approach to treat type 2 diabetes. In the present study, we applied an antisense oligonucleotide (ASO) against GCCR (ASO-GCCR) to reduce the expression of liver GCCR and examined its impact on the diabetic syndrome in ob / ob and db / db mice. A 3-week treatment regimen of ASO-GCCR (25 mg/kg IP, twice per week) markedly reduced liver GCCR messenger RNA and protein expression with no alteration of GCCR messenger RNA expression in the hypothalamus, pituitary, or adrenal gland. The ASO-GCCR treatment lowered blood glucose levels by 45% and 23% in ob / ob and db / db mice, respectively, compared with those observed in the control group. The ASO-GCCR-treated mice also showed significant enhancement of insulin-mediated inhibition of hepatic glucose production during a euglycemic-hyperinsulinemic clamp as well as marked reduction of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase activity compared with control mice. The ASO-GCCR treatment did not change peripheral insulin sensitivity during the clamp. The ob / ob mice treated with ASO-GCCR had no significant difference in the plasma corticosterone and corticotropin levels compared with control mice. Lean mice receiving a similar treatment regimen of ASO-GCCR exhibited no change in blood glucose levels, oral glucose tolerance tests, or insulin tolerance tests. Our results demonstrate that selective inhibition of GCCR expression in the liver by the ASO-GCCR treatment reduced hepatic glucose production and improved blood glucose control under diabetic conditions.
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PMID:Antisense oligonucleotides targeted against glucocorticoid receptor reduce hepatic glucose production and ameliorate hyperglycemia in diabetic mice. 1598 91

The hepatic transcriptional regulation by glucocorticoids of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C) gene is coordinated by interactions of specific transcription factors at the glucocorticoid regulatory unit (GRU). We propose an extended GRU that consists of four accessory sites, two proximal AF1 and AF2 sites and their distal counterpart dAF1 (-993) and a new site, dAF2 (-1365); together, these four sites form a palindrome. Sequencing and gel shift binding assays of hepatic nuclear proteins interacting with these sites indicated similarity of dAF1 and dAF2 sites to the GRU proximal AF1 and AF2 sites. Chromatin immunoprecipitation assays demonstrated that glucocorticoids enhanced the binding of FOXO1 and peroxisome proliferator-activated receptor-alpha to AF2 and dAF2 sites and not to dAF1 site but enhanced the binding of hepatic nuclear transcription factor-4alpha only to the dAF1 site. Insulin inhibited the binding of these factors to their respective sites but intensified the binding of phosphorylated FOXO1. Transient transfections in HepG2 human hepatoma cells showed that glucocorticoid receptor interacts with several non-steroid nuclear receptors, yielding a synergistic response of the PEPCK-C gene promoter to glucocorticoids. The synergistic stimulation by glucocorticoid receptor together with peroxisome proliferator-activated receptor-alpha or hepatic nuclear transcription factor-4alpha requires all four accessory sites, i.e. a mutation of each of these markedly affects the synergistic response. Mice with a targeted mutation of the dAF1 site confirmed this requirement. This mutation inhibited the full response of hepatic PEPCK-C gene to diabetes by reducing PEPCK-C mRNA level by 3.5-fold and the level of circulating glucose by 25%.
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PMID:Glucocorticoids regulate transcription of the gene for phosphoenolpyruvate carboxykinase in the liver via an extended glucocorticoid regulatory unit. 1610 Jan 17

Glucocorticoids play pivotal roles in the maintenance of homeostasis but, when dysregulated, may also have deleterious effects. Smad6, one of the transforming growth factor beta (TGFbeta) family downstream transcription factors, interacts with the N-terminal domain of the glucocorticoid receptor (GR) through its Mad homology 2 domain and suppresses GR-mediated transcriptional activity in vitro. Adenovirus-mediated Smad6 overexpression inhibits glucocorticoid action in rat liver in vivo, preventing dexamethasone-induced elevation of blood glucose levels and hepatic mRNA expression of phosphoenolpyruvate carboxykinase, a well known rate-limiting enzyme of liver gluconeogenesis. Smad6 suppresses GR-induced transactivation by attracting histone deacetylase 3 to DNA-bound GR and by antagonizing acetylation of histone H3 and H4 induced by p160 histone acetyltransferase. These results indicate that Smad6 regulates glucocorticoid actions as a corepressor of the GR. From our results and known cross-talks between glucocorticoids and TGFbeta family molecules, it appears that the anti-glucocorticoid actions of Smad6 may contribute to the neuroprotective, anticatabolic and pro-wound healing properties of the TGFbeta family of proteins.
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PMID:The Smad6-histone deacetylase 3 complex silences the transcriptional activity of the glucocorticoid receptor: potential clinical implications. 1624 87

Thyroid hormone receptors (TRs) are ligand-regulated transcription factors that bind to thyroid hormone response elements of target genes. Upon ligand binding, they recruit coactivator complexes that increase histone acetylation and recruit RNA polymerase II (Pol II) to activate transcription. Recent studies suggest that nuclear receptors and coactivators may have temporal recruitment patterns on hormone response elements, yet little is known about the nature of the patterns at multiple endogenous target genes. We thus performed chromatin immunoprecipitation assays to investigate coactivator recruitment and histone acetylation patterns on the thyroid hormone response elements of four endogenous target genes (GH, sarcoplasmic endoplasmic reticulum calcium-adenosine triphosphatase, phosphoenolpyruvate carboxykinase, and cholesterol 7alpha-hydroxylase) in a rat pituitary cell line that expresses TRs. We found that TRbeta, several associated coactivators (steroid receptor coactivator-1, glucocorticoid receptor interacting protein-1, and TR-associated protein 220), and RNA Pol II were rapidly recruited to thyroid hormone response elements as early as 15 min after T3 addition. When the four target genes were compared, we observed differences in the types and temporal patterns of recruited coactivators and histone acetylation. Interestingly, the temporal pattern of RNA Pol II was similar for three genes studied. Our findings suggest that thyroid hormone-regulated target genes may have distinct patterns of coactivator recruitment and histone acetylation that may enable highly specific regulation.
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PMID:Thyroid hormone-regulated target genes have distinct patterns of coactivator recruitment and histone acetylation. 1625 15

In the present paper, we examine how arsenic species accumulate in fish liver and explore the hypothesis that sublethal arsenic concentrations in fish hepatic tissue interfere with stress-mediated gene expression. We exposed killifish (Fundulus heteroclitus) to 787 or 0 microg/L arsenic in tank water for 2 weeks. Arsenic exposure elevated total liver arsenic from 3.4 microg/g wet weight (control fish) to 9.6 microg/g wet weight, and resulted in a higher relative proportion of toxic (e.g. monomethylarsenous acid, dimethylarsenous acid, arsenic V) versus benign (arsenobetaine) arsenic species in this tissue. Following the exposure period, arsenic-treated and control fish were then subjected to a stress protocol: confinement and mechanical chasing for 15 min every 3 h. Liver tissue and blood were sampled from fish not exposed to the stressor at time 0, and at 8, 12, 24 and 40 h following the first stressor. Concentrations of the stress hormone cortisol increased significantly, and glucocorticoid receptor mRNA levels increased and then decreased in both groups, but patterns were nearly identical between arsenic pre-treated and arsenic untreated fish. Prior arsenic exposure prevented the stress-induced increases in stress-responsive LDH-B mRNA levels and enzyme activity observed in fish that had not been exposed to arsenic. However, in another stress-responsive gene, PEPCK, arsenic did not interfere with the stress-induced increase in gene expression, suggesting that the effects of arsenic on stress-mediated gene expression are complex and may involve regulatory pathways that differ between these two genes.
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PMID:Arsenic exposure alters hepatic arsenic species composition and stress-mediated gene expression in the common killifish (Fundulus heteroclitus). 1644 94

Anadromous arctic char (Salvelinus alpinus) undertake short feeding migrations to seawater every summer and accumulate lipids, while the rest of the year is spent in fresh water where the accumulated lipid reserves are mobilized. We tested the hypothesis that winter fasting and the associated polychlorinated biphenyls' (PCBs) redistribution from lipid depots to critical tissues impair the liver metabolic capacity in these animals. Char were administered Aroclor 1254 (0, 1, 10, and 100 mg/kg body mass) orally and maintained for 4 months without feeding to mimic seasonal winter fasting, while fed groups (0 and 100 mg Aroclor 1254/kg) were maintained for comparison. A clear dose-related increase in PCB accumulation and cytochrome P4501A (CYP1A) protein content was observed in the livers of fasted fish. This PCB concentration and CYP1A response with the high dose of Aroclor were 1.5-fold and 3-fold greater in the fasted than in the fed fish, respectively. In fed fish, PCB exposure lowered liver glycogen content, whereas none of the other metabolic indicators were significantly affected. In fasted fish, PCB exposure depressed liver glycogen content and activities of glucose-6-phosphate dehydrogenase, alanine aminotransferase, lactate dehydrogenase, and phosphoenolpyruvate carboxykinase and elevated 3-hydroxyacylcoA dehydrogenase activity and glucocorticoid receptor protein expression. There were no significant impacts of PCB on heat shock protein 70 (hsp70) and hsp90 contents in either fed or fasted fish. Collectively, our study demonstrates that winter emaciation associated with the anadromous lifestyle predisposes arctic char to PCB impact on hepatic metabolism including disruption of the adaptive metabolic responses to extended fasting.
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PMID:Fasting augments PCB impact on liver metabolism in anadromous arctic char. 1653 58

Recent epidemiological studies demonstrated a beneficial effect of coffee consumption for the prevention of type 2 diabetes, however, the underlying mechanisms remained unknown. We demonstrate that coffee extract, corresponding to an Italian Espresso, inhibits recombinant and endogenous 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity. The inhibitory component is heat-stable with considerable polarity. Coffee extract blocked 11beta-HSD1-dependent cortisol formation, prevented the subsequent nuclear translocation of the glucocorticoid receptor and abolished glucocorticoid-induced expression of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase. We suggest that at least part of the anti-diabetic effects of coffee consumption is due to inhibition of 11beta-HSD1-dependent glucocorticoid reactivation.
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PMID:Coffee inhibits the reactivation of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1: a glucocorticoid connection in the anti-diabetic action of coffee? 1681 82

To assess the effects of subordinate social status on digestive function, metabolism, and enzyme activity in salmonid fish, juvenile rainbow trout Oncorhynchus mykiss were paired with size-matched conspecifics (<1.5% difference in fork length) for 5 d. Fish that were fasted for 5 d and fish sampled directly from the holding tank were used as control groups. Both subordinate and fasted fish experienced significant decreases in intestine mass (P = 0.043), and the gall bladder showed marked and significant changes in both size (P = 0.004) and appearance. These findings suggest that the negative effect of social subordination on digestive function reflects in large part a lack of feeding. Hepatic phosphoenolpyruvate carboxykinase activity was significantly higher in subordinate fish relative to dominants, whereas subordinate hepatic pyruvate kinase activity was significantly lower; activities of both enzymes were significantly correlated with plasma cortisol concentrations and behavior scores. Dominant-subordinate differences in the activities of these enzymes were eliminated by administration of the glucocorticoid receptor antagonist RU486, underlining a role for circulating cortisol in eliciting the differences. Significant increases relative to control fish were also detected in red and white muscles from subordinate fish in the activities of protein catabolic enzymes (aspartate aminotransferase, alanine aminotransferase, glutamate dehydrogenase). These differences occurred in the absence of any change in plasma free amino acid or ammonia concentrations, supporting an enhanced turnover of amino acids in muscle in subordinate fish. The results support the hypothesis that changes in metabolism, beyond those elicited by low food consumption, may be responsible at least in part for the low growth rates typical of subordinate fish and that these changes may be related specifically to circulating cortisol levels in subordinate fish.
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PMID:Growth depression in socially subordinate rainbow trout Oncorhynchus mykiss: more than a fasting effect. 1682 94

The glucocorticoid receptor (GR) is a crucial target gene for glucocorticoid-induced insulin resistance and hepatic gluconeogenesis linked to the development of type 2 diabetes. The liver X receptors (LXRs) are nuclear receptors that play an important role in the regulation of the metabolic gene linked to carbohydrate homeostasis. To assess the tissue-specific interaction of LXR with GR in the development of type 2 diabetes, we examined the possible effect of LXR agonist T0901317 on GR gene expression in vivo and in vitro in hepatocytes from db/db mice (a model of type 2 diabetes). Chronic ligand activation of LXR by a synthetic LXR T0901317 markedly decreased the expression of both GR mRNA and its protein in liver and improved the phenotype of type 2 diabetes in obese db/db mice. Suppression of hepatic GR expression was correlated with reduced levels of glucose and corresponded to the inhibition of phosphoenolpyruvate carboxykinase mRNA and 11beta-hydroxysteroid dehydrogenase type 1-mediated synthesis of active corticosterone from inactive 11-dehydrocorticosterone in liver. Treatment of db/db mouse primary hepatocytes with T0901317 resulted in dramatic suppression of GR mRNA and required ongoing protein synthesis. Addition of T0901317 to primary hepatocytes also suppressed the expression of both 11beta-hydroxysteroid dehydrogenase type 1 and phosphoenolpyruvate carboxykinase. These findings suggest that some of antidiabetic actions of LXR agonist T0901317 may be mediated, at least in part, through the suppression of hepatic GR gene expression.
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PMID:Liver X receptor agonist T0901317 inhibition of glucocorticoid receptor expression in hepatocytes may contribute to the amelioration of diabetic syndrome in db/db mice. 1687 40


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