The inhibitory effect of glucose on phosphoenolpyruvate carboxykinase gene expression in cultured hepatocytes is transcriptional and requires glucose metabolism

Cournarie, Fabienne; Azzout‐Marniche, Dalila; Foretz, Marc; Guichard, C; Ferré, Pascal; Foufelle, Fabienne

doi:10.1016/s0014-5793(99)01407-6

Cited by 34 publications

(26 citation statements)

References 35 publications

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“…It has been already noted that the overexpression of GK can decrease PEPCK expression in diabetic mice (15). This was attributed to an inhibitory effect of a GKmediated increased glucose metabolism, because glucose or one of its metabolites represses PEPCK promoter activity (34,35). In the present study, because of the increased GK activity, a glucose effect could certainly contribute to the strong decrease of PEPCK expression and activity.…”

Section: Resultssupporting

confidence: 57%

Adenovirus-Mediated Overexpression of Sterol Regulatory Element Binding Protein-1c Mimics Insulin Effects on Hepatic Gene Expression and Glucose Homeostasis in Diabetic Mice

et al. 2001

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In vitro, the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) mimics the positive effects of insulin on hepatic genes involved in glucose utilization, such as glucokinase (GK) and enzymes of the lipogenic pathway, suggesting that it is a key factor in the control of hepatic glucose metabolism. Decreased glucose utilization and increased glucose production by the liver play an important role in the development of the hyperglycemia in diabetic states. We thus reasoned that if SREBP-1c is indeed a mediator of hepatic insulin action, a hepatic targeted overexpression of SREBP-1c should greatly improve glucose homeostasis in diabetic mice. This was achieved by injecting streptozotocin-induced diabetic mice with a recombinant adenovirus containing the cDNA of the mature, transcriptionally active form of SREBP-1c. We show here that overexpressing SREBP-1c specifically in the liver of diabetic mice induces GK and lipogenic enzyme gene expression and represses the expression of phosphoenolpyruvate carboxykinase, a key enzyme of the gluconeogenic pathway. This in turn increases glycogen and triglyceride hepatic content and leads to a marked decrease in hyperglycemia in diabetic mice. We conclude that SREBP-1c has a major role in vivo in the long-term control of glucose homeostasis by insulin.

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Section: Resultssupporting

confidence: 57%

Adenovirus-Mediated Overexpression of Sterol Regulatory Element Binding Protein-1c Mimics Insulin Effects on Hepatic Gene Expression and Glucose Homeostasis in Diabetic Mice

et al. 2001

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“…It has been determined that the proximal promoter (K477 to K1 bp) contains the sequences required for positive regulation of PEPCK, and that this region also contains sequences that are necessary for glucose-mediated inhibition (Cournarie et al 1999). Additional elements upstream contribute to the magnitude of the transcriptional activation by glucocorticoids; however, they are not necessary for activation.…”

Section: Discussionmentioning

confidence: 99%

Larval zebrafish as a model for glucose metabolism: expression of phosphoenolpyruvate carboxykinase as a marker for exposure to anti-diabetic compounds

Elo¹,

Villano²,

Govorko³

et al. 2007

Journal of Molecular Endocrinology

140

121

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The zebrafish model system is one of the most widely used animal models for developmental research and it is now becoming an attractive model for drug discovery and toxicological screening. The completion of sequencing the zebrafish genome and the availability of full-length cDNAs and DNA microarrays for expression analysis, in addition to techniques for generating transgenic lines and targeted mutations, have made the zebrafish model even more attractive to researchers. Recent data indicate that the regulation of glucose metabolism in zebrafish, through the production of insulin, is similar to mammalian models, and many of the genes involved in regulating blood glucose levels have been identified in zebrafish. The data presented here show that adult zebrafish respond to anti-diabetic drugs similarly to mammalian models, by reducing blood glucose levels. Furthermore, we show that the expression of phosphoenolpyruvate carboxykinase (PEPCK), which catalyzes a rate-limiting step in gluconeogenesis and is transcriptionally regulated by glucagon and insulin, is regulated in larval zebrafish similarly to that seen in mammalian systems, and changes in PEPCK expression can be obtained through real-time PCR analysis of whole larval RNA. Taken together, these data suggest that larval zebrafish may be an appropriate model for the examination of glucose metabolism, using PEPCK as an indicator of blood glucose levels.

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“…HL1C cells transduced with AdCMV-GKL and either AdCMV-␤Gal or Ad-CMV-ASmyc were used for this purpose. Glycerol was added to the medium as a gluconeogenic substrate to bypass the PEPCK reaction (conversion of oxaloacetate to phosphoenolpyruvate) because the gene encoding this enzyme is known to be repressed by glucose metabolism (6,7). Under these conditions, glycerol enters the gluconeogenic pathway at the triose level, and glucose production should increase with increasing Glc-6-Pase activity despite a reduction in PEPCK activity.…”

Section: C-myc and Glucose-regulated Gene Expressionmentioning

confidence: 99%

“…Glucose metabolism provides a signal that leads to transcriptional repression of the PEPCK gene in HL1C cells (6,7). We sought to determine whether diminishing c-Myc protein levels alleviated the glucose-mediated repression of PEPCK promoter activity.…”

Section: Reducing C-myc Protein Levels In Hl1c Rat Hepatoma Cells Doementioning

confidence: 99%

“…For example, the L-pyruvate kinase (L-PK) and glucose-6-phosphatase (Glc-6-Pase) genes (encoding key glycolytic and gluconeogenic enzymes, respectively) are stimulated by increases in hepatic glucose metabolism (3)(4)(5). Conversely, glucose metabolism can also negatively regulate gene transcription, exemplified by the repression of hormone-activated phosphoenolpyruvate carboxykinase (PEPCK) gene promoter activity (6,7). Although glucose metabolism modulates the gene expression patterns of key glycolytic and gluconeogenic enzymes, the signaling mechanisms and coordinating transcription factors involved are not fully characterized.…”

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c-Myc Is Required for the Glucose-mediated Induction of Metabolic Enzyme Genes

Collier

Doan²,

Daniels³

et al. 2003

Journal of Biological Chemistry

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Glucose exerts powerful effects on hepatocyte gene transcription by mechanisms that are incompletely understood. c-Myc regulates hepatic glucose metabolism by increasing glycolytic enzyme gene transcription while concomitantly decreasing gluconeogenic and ketogenic enzyme gene expression. However, the molecular mechanisms by which c-Myc exerts these effects is not known. In this study, the glucose-mediated induction of L-type pyruvate kinase and glucose-6-phosphatase mRNA levels was diminished by maneuvers involving recombinant adenoviral vectors that interfere with (i) c-Myc protein levels by antisense expression or (ii) c-Myc function through a dominant-negative Max protein. These results were obtained using both HL1C rat hepatoma cells and primary rat hepatocytes. Furthermore, a decrease in c-Myc abundance reduced glucose production in HL1C cells, presumably by decreasing glucose-6-phosphatase activity. The repression of hormone-activated phosphoenolpyruvate carboxykinase gene transcription by glucose was not affected by a reduction in c-Myc levels. The basal mRNA levels for Lpyruvate kinase and glucose-6-phosphatase were not altered to any significant degree by adenoviral treatment. Furthermore, adenoviral overexpression of the c-Myc protein induced glucose-6-phosphatase mRNA in the absence of glucose stimulation. We conclude that multiple mechanisms exist to communicate the glucose-derived signal and that c-Myc has a key role in the hepatic glucose signaling pathway.Insulin and glucose act jointly to influence glucose homeostasis by altering hepatic gene expression patterns. Insulin increases glucokinase (GK) 1 gene transcription and protein levels in hepatocytes (1). The phosphorylation of glucose by GK leads to increased glucose flux and metabolism, generating signaling metabolites that modify the gene expression profile of the liver (2). For example, the L-pyruvate kinase (L-PK) and glucose-6-phosphatase (Glc-6-Pase) genes (encoding key glycolytic and gluconeogenic enzymes, respectively) are stimulated by increases in hepatic glucose metabolism (3-5). Conversely, glucose metabolism can also negatively regulate gene transcription, exemplified by the repression of hormone-activated phosphoenolpyruvate carboxykinase (PEPCK) gene promoter activity (6, 7). Although glucose metabolism modulates the gene expression patterns of key glycolytic and gluconeogenic enzymes, the signaling mechanisms and coordinating transcription factors involved are not fully characterized.One transcription factor that is a candidate for establishing hepatic glucose-dependent gene expression patterns is the basic, helix-loop-helix leucine-zipper (bHLH-LZ) transcription factor c-Myc (8, 9). The Myc family of proteins (e.g. c-, N-, L-Myc, USF, Max, Mad, etc.) participates in control of proliferation, growth, differentiation, apoptosis, and metabolism (10, 11). c-Myc binds DNA by interacting with the E box sequence CACGTG (and other related non-canonical sites) as a heterodimer with Max, another bHLH-LZ protein. The Myc/Max heterodimer ...

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The inhibitory effect of glucose on phosphoenolpyruvate carboxykinase gene expression in cultured hepatocytes is transcriptional and requires glucose metabolism

Cited by 34 publications

References 35 publications

Adenovirus-Mediated Overexpression of Sterol Regulatory Element Binding Protein-1c Mimics Insulin Effects on Hepatic Gene Expression and Glucose Homeostasis in Diabetic Mice

Adenovirus-Mediated Overexpression of Sterol Regulatory Element Binding Protein-1c Mimics Insulin Effects on Hepatic Gene Expression and Glucose Homeostasis in Diabetic Mice

Larval zebrafish as a model for glucose metabolism: expression of phosphoenolpyruvate carboxykinase as a marker for exposure to anti-diabetic compounds

c-Myc Is Required for the Glucose-mediated Induction of Metabolic Enzyme Genes

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