CARBON FLUX VIA THE PENTOSE-PHOSPHATE PATHWAY REGULATES THE HEPATIC EXPRESSION OF THE GLUCOSE-6-PHOSPHATASE AND PHOSPHOENOLPYRUVATE CARBOXYKINASE GENES IN CONSCIOUS RATS

Hepatic gene expression of P-enolpyruvate carboxykinase (PEPCK) and gl ucose-6-phosphatase (Glc-6-Pase) is regulated in response to changes i n the availability of substrates, in particular glucose (Glc; Massillo n, D., Barzilai, N., Chen, W., Hu, M., and Rossetti, L., (1996) J. Bio l. Chem. 271, 9871-9874). We investigated the mechanism(s) in consciou s rats. Hyperglycemia per se caused a rapid and marked increase in Glc -6-Pase mRNA abun dance and protein levels. By contrast, hyperglycemia decreased the abundance of PEPCK mRNA, Importantly, inhibition of glu cokinase activity by glucosamine infusion blunted both the stimulation of Glc-6-Pase and the inhibition of PEPCK gene expression by Glc, sug gesting that an intrahepatic signal (metabolite) generated by the meta bolism of glucose at or beyond Glc-6-P was responsible for the regulat ory 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 met abolite can also reproduce the effects of Glc on Glc-6-Pase and PEPCK gene expression in vivo. Xylitol, which is directly converted to xylul ose-5-P in the liver, was infused to raise the hepatic concentration o f xylulose-5-P by similar to 3-fold. Xylitol infusion did not alter th e levels of Glc-6-P and of fructose-2,6-biphosphate. However, it repli cated the effects of hyperglycemia on Glc-6-Pase and PEPCK gene expres sion and resulted in a 75% increase in the in vivo flu through Glc-6-P ase (total glucose output).