Carbon flux via the pentose phosphate pathway regulates the hepatic expression of the glucose-6-phosphatase and phosphoenolpyruvate carboxykinase genes in conscious rats

Duna Massillon, Wei Chen, Nir Barzilai, Dina Prus-Wertheimer, Meredith A. Hawkins, Rong Liu, Rebecca Taub, Luciano Rossetti

Research output: Contribution to journalArticle

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Abstract

Hepatic gene expression of P-enolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (Glc-6-Pase) is regulated in response to changes in the availability of substrates, in particular glucose (Glc; Massilion, D., Barzilai, N., Chen, W., Hu, M., and Rossetti, L. (1996) J. Biol. Chem. 271, 9871-9874). We investigated the mechanism(s) in conscious rats. Hyperglycemia per se caused a rapid and marked increase in Glc-6-Pase mRNA abundance and protein levels. By contrast, hyperglycemia decreased the abundance of PEPCK mRNA. Importantly, inhibition of glucokinase activity by glucosamine infusion blunted both the stimulation of Glc-6-Pase and the inhibition of PEPCK gene expression by Glc, suggesting that an intrahepatic signal (metabolite) generated by the metabolism of glucose at or beyond Glc-6-P was responsible for the regulatory effect of Glc. The effect of Glc on the L-type pyruvate kinase gene is mediated by xylulose-5-P (Doiron, B., Cuif, M., Chen, R., and Kahn, A. (1996) J. Biol. Chem. 271, 5321-5324). Thus, we next investigated whether an isolated increase in the hepatic concentration of this metabolite can also reproduce the effects of Glc on Glc-6-Pase and PEPCK gene expression in vivo. Xylitol, which is directly converted to xylulose-5-P in the liver, was infused to raise the hepatic concentration of xylulose-5-P by ~3-fold. Xylitol infusion did not alter the levels of Glc-6-P and of fructose-2,6- biphosphate. However, it replicated the effects of hyperglycemia on Glc-6- Pase and PEPCK gene expression and resulted in a 75% increase in the in vivo flux through Glc-6-Pase (total glucose output).

Original languageEnglish (US)
Pages (from-to)228-234
Number of pages7
JournalJournal of Biological Chemistry
Volume273
Issue number1
DOIs
StatePublished - Jan 2 1998

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Pentoses
Carbon Cycle
Pentose Phosphate Pathway
Glucose-6-Phosphatase
Phosphoenolpyruvate
Xylulose
Rats
Carbon
Gene expression
Genes
Phosphates
Fluxes
Hyperglycemia
Liver
Xylitol
Gene Expression
Metabolites
Glucose
Glucokinase
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry

Cite this

Carbon flux via the pentose phosphate pathway regulates the hepatic expression of the glucose-6-phosphatase and phosphoenolpyruvate carboxykinase genes in conscious rats. / Massillon, Duna; Chen, Wei; Barzilai, Nir; Prus-Wertheimer, Dina; Hawkins, Meredith A.; Liu, Rong; Taub, Rebecca; Rossetti, Luciano.

In: Journal of Biological Chemistry, Vol. 273, No. 1, 02.01.1998, p. 228-234.

Research output: Contribution to journalArticle

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abstract = "Hepatic gene expression of P-enolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (Glc-6-Pase) is regulated in response to changes in the availability of substrates, in particular glucose (Glc; Massilion, D., Barzilai, N., Chen, W., Hu, M., and Rossetti, L. (1996) J. Biol. Chem. 271, 9871-9874). We investigated the mechanism(s) in conscious rats. Hyperglycemia per se caused a rapid and marked increase in Glc-6-Pase mRNA abundance and protein levels. By contrast, hyperglycemia decreased the abundance of PEPCK mRNA. Importantly, inhibition of glucokinase activity by glucosamine infusion blunted both the stimulation of Glc-6-Pase and the inhibition of PEPCK gene expression by Glc, suggesting that an intrahepatic signal (metabolite) generated by the metabolism of glucose at or beyond Glc-6-P was responsible for the regulatory effect of Glc. The effect of Glc on the L-type pyruvate kinase gene is mediated by xylulose-5-P (Doiron, B., Cuif, M., Chen, R., and Kahn, A. (1996) J. Biol. Chem. 271, 5321-5324). Thus, we next investigated whether an isolated increase in the hepatic concentration of this metabolite can also reproduce the effects of Glc on Glc-6-Pase and PEPCK gene expression in vivo. Xylitol, which is directly converted to xylulose-5-P in the liver, was infused to raise the hepatic concentration of xylulose-5-P by ~3-fold. Xylitol infusion did not alter the levels of Glc-6-P and of fructose-2,6- biphosphate. However, it replicated the effects of hyperglycemia on Glc-6- Pase and PEPCK gene expression and resulted in a 75{\%} increase in the in vivo flux through Glc-6-Pase (total glucose output).",
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AU - Prus-Wertheimer, Dina

AU - Hawkins, Meredith A.

AU - Liu, Rong

AU - Taub, Rebecca

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