Carbon Flux via the Pentose Phosphate Pathway Regulates the Hepatic Expression of the Glucose-6-phosphatase and Phosphoenolpyruvate Carboxykinase Genes in Conscious Rats

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; Massillon, 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 approximately 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).