Insulin and cyclic AMP act at different levels on transcription of the L‐type pyruvate kinase gene

Cuif, Marie Hélène; Doiron, Bruno; Kahn, Axel

doi:10.1016/s0014-5793(97)01260-x

Cited by 6 publications

(6 citation statements)

References 27 publications

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“…As previously reported [14–21], the −183PK construct was stimulated by glucose about seven‐fold and inhibited by cAMP about 11‐fold. The glucose‐dependent stimulation was also totally abolished by cotransfection with the PKA expression vector (Fig.…”

Section: Resultssupporting

confidence: 85%

“…Transcription of the L‐PK gene is stimulated by glucose and inhibited by glucagon acting through its second messenger, cAMP. The inhibition of the L‐PK gene by cAMP was shown to involve the classical PKA signaling pathway since the cAMP effect could be reproduced by overexpression of the PKA catalytic subunit [21]. We have previously shown that the in vivo transcriptional inhibition by glucagon of glucose responsive genes in the liver was a very rapid phenomenon, detectable in only a few minutes by run‐on transcription assays [1], contrasting with the activation by glucose which is delayed for several hours [23].…”

Section: Discussionmentioning

confidence: 99%

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Negative cyclic AMP response elements in the promoter of the L‐type pyruvate kinase gene

et al. 1999

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L-type pyruvate kinase gene expression is modulated by hormonal and nutritional conditions. Here, we show by transient transfections in hepatocytes in primary culture that both the glucose response element and the contiguous hepatocyte nuclear factor 4 (HNF4) binding site (L3) of the promoter were negative cyclic AMP (cAMP) response elements and that cAMP-dependent inhibition through L3 requires HNF4 binding. Another HNF4 binding site-dependent construct was also inhibited by cAMP. However, HNF4 mutants whose putative PKA-dependent phosphorylation sites have been mutated still conferred cAMP-sensitive transactivation of a L3-dependent reporter gene. Overexpression of the CREB binding protein (CBP) increased the HNF4-dependent transactivation but this effect remained sensitive to cAMP inhibition.z 1999 Federation of European Biochemical Societies.

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Section: Resultssupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Negative cyclic AMP response elements in the promoter of the L‐type pyruvate kinase gene

et al. 1999

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“…Regulation of cAMP levels by glucagon, insulin, and catecholamines accounts in large part for minute-to-minute hormonal control of pathway flux in fed animals and during the transition from fed to starved. cAMP plays a key role in the regulation of gene transcription of gluconeogenic and lipolytic enzymes: it enhances the transcription of genes encoding hepatic enzymes, such as PEPCK, which in turn induces glucose production (7,30) and negatively regulates the transcription of L-PK gene, a key enzyme of glycolysis (5). In the liver, GK activity is regulated at the level of gene transcription in response to fasting and refeeding (15,22), and its transcription is negatively regulated by glucagon through increases in cAMP concentration (13,14,31,32).…”

Section: Discussionmentioning

confidence: 99%

“…5) gene transcription in the liver of the F28 mice compared with Co mice might be caused by the increased hepatic basal adenylyl cyclase activity. cAMP is known to negatively regulate the L-PK gene transcription (5,14). The decreased L-PK gene transcription is consistent with a decreased glycolytic flux and fits the strongly increased expression of the gluconeogenetic enzyme PEPCK (Fig.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of β₂-adrenergic receptors in mouse liver alters the expression of gluconeogenic and glycolytic enzymes

Erraji-Benchekroun

Postic

Borde

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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.-In the livers of humans and many other mammalian species, ␤ 2-adrenergic receptors (␤2-ARs) play an important role in the modulation of glucose production by glycogenolysis and gluconeogenesis. In male mice and rats, however, the expression and physiological role of hepatic ␤ 2-ARs are rapidly lost with development under normal physiological conditions. We previously described a line of transgenic mice, F28 (André C, Erraji L, Gaston J, Grimber G, Briand P, and Guillet JG. Eur J Biochem 241: [417][418][419][420][421][422][423][424] 1996), which carry the human ␤ 2-AR gene under the control of its own promoter. In these mice, hepatic ␤ 2-AR levels are shown to increase rapidly after birth and, as in humans, be maintained at an elevated level in adulthood. F28 mice display strongly enhanced adenylyl cyclase responses to ␤-AR agonists in their livers and, compared with normal mice, have increased basal hepatic adenylyl cyclase activity. In this report we demonstrate that, under normal physiological conditions, this increased ␤ 2-AR activity affects the expression of the gluconeogenic and glycolytic key enzymes phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and L-pyruvate kinase and considerably decreases hepatic glycogen levels. Furthermore, we show that the effects of ␤-adrenergic ligands on liver glycogen observed in humans are reproduced in these mice: liver glycogen levels are strongly decreased by the ␤ 2-AR agonist clenbuterol and increased by the ␤-AR antagonist propranolol. These transgenic mice open new perspectives for studying in vivo the hepatic ␤2-AR system physiopathology and for testing the effects of ␤-AR ligands on liver metabolism.␤-adrenergic receptor; glycogen; glucose; phosphoenolpyruvate carboxykinase; L-pyruvate kinase THE INTERACTION OF CIRCULATING CATECHOLAMINES with adrenergic receptors plays an important role in the regulation of lipid, protein, and carbohydrate metabolism. Epinephrine enhances lipolysis in adipose tissue, glycogenolysis in muscle, and glucose production in liver that result from both direct stimulation of glycogenolysis and indirect stimulation of gluconeogenesis (3,21,26).Both ␣ 1 -and ␤ 2 -adrenergic receptors (␣ 1 -ARs and ␤ 2 -ARs) are expressed in the liver and are involved in the direct effect of catecholamines. Whereas ␣ 1 -ARs are linked to the phosphoinositide turnover/calcium mobilization, ␤ 2 -ARs mediate their effects via the adenylyl cyclase/cAMP-signaling pathway. The relative contribution of the two adrenergic receptor subtypes to catecholamine-induced glycogenolysis depends on animal species, sex, and physiological state (16,19).In the livers of most species, including humans, the number of both ␣ 1 -and ␤ 2 -ARs is high, and catecholamine-stimulated glycogenolysis occurs primarily via ␤ 2 -ARs in normal physiological conditions (3,17,21,26,28,34). In male rats and mice, however, there is a reversal in predominance from ␤ 2 -ARs to ␣ 1 -ARs during development. The ␤ 2 -AR density, ␤ 2 -AR-induced cAMP responses, and ␤ 2 -AR-dependent glycogen...

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“…At this level, the expression of genes for GK, 6PFK2/FBP2, 6PFK1, and PK are stimulated by either glucose or insulin [32,33], whereas expression of genes for PEPCK, FBPase, and G6Pase are repressed [34,35]. Fasting reverses these changes that suppress HGP during feeding.…”

Section: Regulation Of Hepatic Glucose Productionmentioning

confidence: 99%

Reduction of Hepatic Glucose Production as a Therapeutic Target in the Treatment of Diabetes

Wu¹,

Okar²,

Kang³

et al. 2005

curr drug targets immune endocr metabol disord

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There has been an alarming increase in the population diagnosed with diabetes worldwide. Although there is an ongoing debate as to the role of liver in the pathogenesis of diabetes, reduction of hepatic glucose production has been targeted as a strategy for diabetes treatment. Indeed, reduction of hepatic glucose production can be achieved through modulation of both hepatic and extra-hepatic targets. This review describes the role of the liver in the control of glucose homeostasis. Gluconeogenesis and glycogenolysis are pathways for glucose production, whereas glycolysis and glycogenesis are pathways for glucose utilization/storage. At the biochemical and molecular level, the metabolic and regulatory enzymes integrate hormonal and nutritional signals and regulate glucose flux in the liver. Modulating either activities of or gene expression of these metabolic enzymes can control hepatic glucose production. Dysfunction of one or several enzyme(s) due to insulin deficiency or resistance results in increases in fluxes of glycogenolysis and gluconeogenesis and/or decreases in fluxes of glycolysis and glycogenesis, which thereby lead to glucose generation exceeding glucose consumption/disposal, as well as dysregulation of lipid metabolism. Activation of enzymes that promote glucose utilization/storage and/or inhibition of enzymes that reduce glucose generation achieve reduction of hepatic glucose production, and hence lower levels of plasma glucose in diabetes. This is also beneficial for the correction of dyslipidemia. Therefore, many enzymes are viable therapeutic targets for diabetes.

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Insulin and cyclic AMP act at different levels on transcription of the L‐type pyruvate kinase gene

Cited by 6 publications

References 27 publications

Negative cyclic AMP response elements in the promoter of the L‐type pyruvate kinase gene

Negative cyclic AMP response elements in the promoter of the L‐type pyruvate kinase gene

Overexpression of β₂-adrenergic receptors in mouse liver alters the expression of gluconeogenic and glycolytic enzymes

Reduction of Hepatic Glucose Production as a Therapeutic Target in the Treatment of Diabetes

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Insulin and cyclic AMP act at different levels on transcription of the L‐type pyruvate kinase gene

Cited by 6 publications

References 27 publications

Negative cyclic AMP response elements in the promoter of the L‐type pyruvate kinase gene

Negative cyclic AMP response elements in the promoter of the L‐type pyruvate kinase gene

Overexpression of β2-adrenergic receptors in mouse liver alters the expression of gluconeogenic and glycolytic enzymes

Reduction of Hepatic Glucose Production as a Therapeutic Target in the Treatment of Diabetes

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Overexpression of β₂-adrenergic receptors in mouse liver alters the expression of gluconeogenic and glycolytic enzymes