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)

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

Rat offspring exposed to ethanol (EtOH rats) during pregnancy are insulin resistant, but it is unknown whether they have increased gluconeogenesis. To address this issue, we determined blood glucose and liver gluconeogenic genes, proteins, and enzyme activities before and after insulin administration in juvenile and adult EtOH rats and submitted adult EtOH rats to a pyruvate challenge. In juvenile rats, basal glucose; peroxisome proliferator-activated receptor-coactivator-1alpha protein and mRNA; and phosphoenolpyruvate carboxykinase enzyme activity, protein, and mRNA were similar between groups. After insulin injection, these parameters failed to decrease in EtOH rats, but glucose decreased by 30% and gluconeogenic enzymes, proteins, and mRNAs decreased by 50-70% in control rats. In adult offspring, basal peroxisome proliferator-activated receptor-coactivator-1alpha protein and mRNA levels were 40-80% higher in EtOH rats than in controls. Similarly, basal phosphoenolpyruvate carboxykinase activity, protein, and mRNA were approximately 1.8-fold greater in EtOH rats than in controls. These parameters decreased by approximately 50% after insulin injection in control rats, but they remained unchanged in EtOH rats. After insulin injection in the adult rats, glucose decreased by 60% in controls but did not decrease significantly in EtOH rats. A subset of adult EtOH rats had fasting hyperglycemia and an exaggerated glycemic response to pyruvate compared with controls. The data indicate that, after prenatal EtOH exposure, the expression of gluconeogenic genes is exaggerated in adult rat offspring and is insulin resistant in both juvenile and adult rats, explaining increased gluconeogenesis. These alterations persist through adulthood and may contribute to the pathogenesis of Type 2 diabetes after exposure to EtOH in utero.
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PMID:Adult rats prenatally exposed to ethanol have increased gluconeogenesis and impaired insulin response of hepatic gluconeogenic genes. 1623 4

Nitric oxide (NO) is synthesized from L-arginine by NO synthase in virtually all cell types. Emerging evidence shows that NO regulates the metabolism of glucose, fatty acids and amino acids in mammals. As an oxidant, pathological levels of NO inhibit nearly all enzyme-catalyzed reactions through protein oxidation. However, as a signaling molecule, physiological levels of NO stimulate glucose uptake as well as glucose and fatty acid oxidation in skeletal muscle, heart, liver and adipose tissue; inhibit the synthesis of glucose, glycogen, and fat in target tissues (e.g., liver and adipose); and enhance lipolysis in adipocytes. Thus, an inhibition of NO synthesis causes hyperlipidemia and fat accretion in rats, whereas dietary arginine supplementation reduces fat mass in diabetic fatty rats. The putative underlying mechanisms may involve multiple cyclic guanosine-3',5'-monophosphate-dependent pathways. First, NO stimulates the phosphorylation of adenosine-3',5'-monophosphate-activated protein kinase, resulting in (1) a decreased level of malonyl-CoA via inhibition of acetyl-CoA carboxylase and activation of malonyl-CoA decarboxylase and (2) a decreased expression of genes related to lipogenesis and gluconeogenesis (glycerol-3-phosphate acyltransferase, sterol regulatory element binding protein-1c and phosphoenolpyruvate carboxykinase). Second, NO increases the phosphorylation of hormone-sensitive lipase and perilipins, leading to the translocation of the lipase to the neutral lipid droplets and, hence, the stimulation of lipolysis. Third, NO activates expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, thereby enhancing mitochondrial biogenesis and oxidative phosphorylation. Fourth, NO increases blood flow to insulin-sensitive tissues, promoting substrate uptake and product removal via the circulation. Modulation of the arginine-NO pathway through dietary supplementation with L-arginine or L-citrulline may aid in the prevention and treatment of the metabolic syndrome in obese humans and companion animals, and in reducing unfavorable fat mass in animals of agricultural importance.
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PMID:Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. 1652 13

Hepatic insulin resistance is one of the characteristics of type 2 diabetes and contributes to the development of hyperglycemia. How changes in hepatic glucose flux lead to insulin resistance is not clearly defined. We determined the effects of decreasing the levels of hepatic fructose 2,6-bisphosphate (F26P(2)), a key regulator of glucose metabolism, on hepatic glucose flux in the normal 129J mice. Upon adenoviral overexpression of a kinase activity-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, the enzyme that determines F26P(2) level, hepatic F26P(2) levels were decreased twofold compared with those of control virus-treated mice in basal state. In addition, under hyperinsulinemic conditions, hepatic F26P(2) levels were much lower than those of the control. The decrease in F26P(2) leads to the elevation of basal and insulin-suppressed hepatic glucose production. Also, the efficiency of insulin to suppress hepatic glucose production was decreased (63.3 vs. 95.5% suppression of the control). At the molecular level, a decrease in insulin-stimulated Akt phosphorylation was consistent with hepatic insulin resistance. In the low hepatic F26P(2) states, increases in both gluconeogenesis and glycogenolysis in the liver are responsible for elevations of hepatic glucose production and thereby contribute to the development of hyperglycemia. Additionally, the increased hepatic gluconeogenesis was associated with the elevated mRNA levels of peroxisome proliferator-activated receptor-gamma coactivator-1alpha and phosphoenolpyruvate carboxykinase. This study provides the first in vivo demonstration showing that decreasing hepatic F26P(2) levels leads to increased gluconeogenesis in the liver. Taken together, the present study demonstrates that perturbation of glucose flux in the liver plays a predominant role in the development of a diabetic phenotype, as characterized by hepatic insulin resistance.
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PMID:Perturbation of glucose flux in the liver by decreasing F26P2 levels causes hepatic insulin resistance and hyperglycemia. 1662 98

Vitamin A deficiency decreases hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene expression in mice and expression is restored with retinoic acid treatment in vivo. This report examines further the mechanism of retinoid regulation of the PEPCK gene in vivo. We have identified nuclear receptors that bind to retinoic acid response elements (RAREs) in the PEPCK promoter by electrophoretic mobility shift assay and have verified these in vivo using chromatin immunoprecipitation (ChIP) in mouse liver. Based on the results of our ChIP assay, hepatic nuclear factor (HNF)-4alpha, retinoid X receptor (RXR) alpha, retinoic acid receptor (RAR) alpha, peroxisome proliferator-activated receptor (PPAR) alpha and chicken ovalbumin upstream promoter transcription factor (COUP-TF) II bind to the downstream retinoic acid response unit RARE1/RARE2, and PPARalpha and RXRalpha bind to the upstream RARE3 of the PEPCK gene. HNF-4alpha, RXRalpha, RARalpha, PPARalpha and COUP-TFII bind PEPCK RAREs in a specific pattern that, with the exception of PPARalpha, does not change significantly with vitamin A deficiency. PPARalpha binding to the upstream retinoic acid response element is decreased in the vitamin A-deficient liver, when compared to the vitamin A-sufficient state. These results provide the first in vivo measures of nuclear receptor binding to the upstream and downstream RAREs of the PEPCK gene under conditions where the nucleosomal structure of the chromatin is maintained and the nuclear receptors are physically cross-linked in situ to the PEPCK DNA in intact liver.
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PMID:Nuclear receptor binding to the retinoic acid response elements of the phosphoenolpyruvate carboxykinase gene in vivo: effects of vitamin A deficiency. 1671 27

HIV infection is associated with abnormal lipid metabolism, body fat redistribution, and altered energy expenditure. The pathogenesis of these complex abnormalities is unclear. Viral protein R (Vpr), an HIV-1 accessory protein, can regulate gene transcription mediated by the glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma and affect mitochondrial function in vitro. To test the hypothesis that expression of Vpr in liver and adipocytes can alter lipid metabolism in vivo, we engineered mice to express Vpr under control of the phosphoenolpyruvate carboxykinase promoter in a tissue-specific and inducible manner and investigated the effects of dietary fat, indinavir, and dexamethasone on energy metabolism and body composition. The transgenic mice expressed Vpr mRNA in white and brown adipose tissues and liver and immunoaffinity capillary electrophoresis revealed that they had free Vpr protein in the plasma. Compared with wild-type (WT) animals, Vpr mice had lower plasma triglyceride levels after 6 wk (P < 0.05) but not after 10 wk of a high-fat diet and lower plasma cholesterol levels after 10 wk of high-fat diet (P < 0.05). Treatment with dexamethasone obviated group differences, whereas indinavir had no significant independent effect on lipids. In the fasted state, Vpr mice had a higher respiratory quotient than WT mice (P < 0.05). These data provide the first in vivo evidence that HIV-1 Vpr expressed at low levels in adipose tissues and liver can 1) circulate in the blood, 2) regulate lipid and fatty acid metabolism, and 3) alter fuel selection for oxidation in the fasted state.
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PMID:Effects of transgenic expression of HIV-1 Vpr on lipid and energy metabolism in mice. 1688 32

Leigh syndrome French Canadian variant (LSFC) is an autosomal recessive neurodegenerative disorder due to mutation in the LRP130 (leucine-rich protein 130 kDa) gene. Unlike classic Leigh syndrome, the French Canadian variant spares the heart, skeletal muscle, and kidneys, but severely affects the liver. The precise role of LRP130 in cytochrome c oxidase deficiency and hepatic lactic acidosis that accompanies this disorder is unknown. We show here that LRP130 is a component of the PGC-1alpha (peroxisome proliferator-activated receptor coactivator 1-alpha) transcriptional coactivator holocomplex and regulates expression of PEPCK (phosphoenolpyruvate carboxykinase), G6P (glucose-6-phosphatase), and certain mitochondrial genes through PGC-1alpha. Reduction of LRP130 in fasted mice via adenoviral RNA interference (RNAi) vector blocks the induction of PEPCK and G6P, and blunts hepatic glucose output. LRP130 is also necessary for PGC-1alpha-dependent transcription of several mitochondrial genes in vivo. These data link LRP130 and PGC-1alpha to defective hepatic energy homeostasis in LSFC, and reveal a novel regulatory mechanism of glucose homeostasis.
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PMID:Defects in energy homeostasis in Leigh syndrome French Canadian variant through PGC-1alpha/LRP130 complex. 1705 Jun 73

Recent studies have suggested that n-3 fatty acids, abundant in fish oil, protect against high-fat diet-induced insulin resistance through peroxisome proliferator-activated receptor (PPAR)-alpha activation and a subsequent decrease in intracellular lipid abundance. To directly test this hypothesis, we fed PPAR-alpha null and wild-type mice for 2 weeks with isocaloric high-fat diets containing 27% fat from either safflower oil or safflower oil with an 8% fish oil replacement (fish oil diet). In both genotypes the safflower oil diet blunted insulin-mediated suppression of hepatic glucose production (P < 0.02 vs. genotype control) and PEPCK gene expression. Feeding wild-type mice a fish oil diet restored hepatic insulin sensitivity (hepatic glucose production [HGP], P < 0.002 vs. wild-type mice fed safflower oil), whereas in contrast, in PPAR-alpha null mice failed to counteract hepatic insulin resistance (HGP, P = NS vs. PPAR-alpha null safflower oil-fed mice). In PPAR-alpha null mice fed the fish oil diet, safflower oil plus fish oil, hepatic insulin resistance was dissociated from increases in hepatic triacylglycerol and acyl-CoA but accompanied by a more than threefold increase in hepatic diacylglycerol concentration (P < 0.0001 vs. genotype control). These data support the hypothesis that n-3 fatty acids protect from high-fat diet-induced hepatic insulin resistance in a PPAR-alpha-and diacylglycerol-dependent manner.
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PMID:n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator-activated receptor-alpha-dependent manner. 1725 Dec 75

Bile acid homeostasis is tightly controlled by the feedback mechanism in which an atypical orphan nuclear receptor (NR), small heterodimer partner (SHP), inactivates several transcription factors. We previously demonstrated that bile acid represses the expression of gluconeogenic genes, including glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), and fructose-1,6-bisphosphatase (FBP1) in an SHP-dependent manner. Recently, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) coactivator-1 (PGC-1) gene, a coactivator of NRs important for gluconeogenic gene expression, was also downregulated by bile acid in wild-type mice but not in farnesoid X receptor- or SHP-null mice. However, the molecular mechanism for the effect of bile acid on PGC-1 gene expression remains unknown. In the present study, a series of reporter assays demonstrated that the promoter activity of PGC-1 via a member of the forkhead transcription factors, Foxo1, FOXO3a, and Foxo4 was downregulated by treatment with chenodeoxicholic acid and with transfected SHP. These results revealed that bile acid inhibits the promoter activity of PGC-1 in an SHP-dependent manner.
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PMID:Bile acid represses the peroxisome proliferator-activated receptor-gamma coactivator-1 promoter activity in a small heterodimer partner-dependent manner. 1739 79

Inhibition of phosphoenolpyruvate carboxykinase (PEPCK) by TNF-alpha contributes to the pathogenesis of hypoglycemia in endotoxin shock. In this study, the molecular mechanism underlying the inhibition was investigated in hepatoma cells (rat H4IIE and human HepG2). PEPCK expression was induced by cAMP, and the induction was reduced by TNF-alpha at protein and mRNA levels in H4IIE cells. The inhibition was observed in the PEPCK gene promoter in a PEPCK-luciferase reporter. Activation of nuclear factor kappaB (NF-kappaB) pathway was required for the transcriptional inhibition of PEPCK gene. Degradation of NF-kappaB inhibitor (IkappaB) and p65 nuclear translocation were involved in the inhibition. An interaction of histone deacetylase 3 (HDAC3) and silencing mediator for retinoic acid receptor and thyroid hormone receptor (SMRT) with the PEPCK gene promoter was induced by TNF-alpha and observed in a chromatin immunoprecipitation assay. The TNF-induced inhibition was blocked by HDAC inhibitor or HDAC3 knockdown. The blocking effect was also observed in knockdown of corepressor SMRT. Point mutation suggests that cAMP response element (CRE) is required for TNF-induced inhibition of the PEPCK gene promoter. Phosphorylation of cAMP response element-binding protein at Ser133 and expression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha were not changed by TNF-alpha in H4IIE cells. The transcriptional activity of CRE-binding protein was inhibited by TNF-alpha in a CRE-luciferase reporter. The data suggests that the nuclear corepressor proteins of HDAC3 and SMRT mediate TNF inhibition of PEPCK transcription. The inhibition mechanism is related to activation of NF-kappaB and inhibition of CRE-binding protein activity by the corepressor. These data suggest a novel activity of nuclear corepressor in the regulation of PEPCK expression by TNF-alpha.
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PMID:Nuclear corepressor is required for inhibition of phosphoenolpyruvate carboxykinase expression by tumor necrosis factor-alpha. 1745 89


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