TRANSCRIPTIONAL GLUCOSE SIGNALING THROUGH THE GLUCOSE RESPONSE ELEMENT IS MEDIATED BY THE PENTOSE-PHOSPHATE PATHWAY

Glucose catabolism induces the expression of the L-type pyruvate kinas e (L-PK) gene through the glucose response element (GIRE). The metabol ic pathway used by glucose after its phosphorylation to glucose 6-phos phate by glucokinase to induce L-PK gene expression in hepatocytes rem ains unknown. The sugar alcohol xylitol is metabolized to xylulose 5-p hosphate, an intermediate of the nonoxidative branch of the pentose ph osphate pathway. In this study, we demonstrated that xylitol at low co ncentration (0.5 mM) induced the expression of the L-PK/CAT construct in glucose-responsive mhAT3F hepatoma cells at the same level as 20 mM glucose, while it did not affect intracellular concentration of gluco se 6-phosphate significantly. The effect of xylitol on the induction o f the L-PK gene expression was noncumulative with that of glucose sinc e 20 mM glucose plus 5 mM xylitol induced the expression of the L-PK/C AT construct similarly to 20 nM glucose alone. In hepatocytes in prima ry culture, 5 mM xylitol induced accumulation of the L-PK mRNA even in the absence of insulin. Furthermore, the response to xylitol as well as glucose required the presence of a functional GIRE. It can be assum ed from these results that glucose induces the expression of the L-PK gene through the nonoxidative branch of the pentose phosphate pathway. The effect of xylitol at low concentration suggests that the glucose signal to the transcriptional machinery is mediated by xylulose 5-phos phate.