INDUCTION OF FATTY-ACID SYNTHASE AND S14 GENE-EXPRESSION BY GLUCOSE, XYLITOL AND DIHYDROXYACETONE IN CULTURED RAT HEPATOCYTES IS CLOSELY CORRELATED WITH GLUCOSE-6-PHOSPHATE CONCENTRATIONS

It is now well established that the transcription of several genes bel onging to the glycolytic and lipogenic pathway is stimulated in the pr esence of a high glucose concentration in adipocytes and hepatocytes. We have previously proposed that glucose 6-phosphate could be the sign al metabolite that transduces the glucose effect. This proposal has re cently been challenged and both an intermediate of the pentose phospha te pathway, xylulose 5-phosphate, and metabolites of the later part of glycolysis (3-phosphoglycerate and phosphoenolpyruvate) have been pro posed. To discriminate between these possibilities, we have measured c oncomitantly, in primary cultures of adult rat hepatocytes, the expres sion of the fatty acid synthase (FAS) and S14 genes and the concentrat ion of glucose metabolites. We have used various substrates entering a t different steps of the glycolytic pathway (glucose, dihydroxyacetone ) and the pentose phosphate pathway (xylitol). When compared with 5 mM glucose, 25 mM glucose induces a marked increase in both S14 and FAS gene expression, detectable as early as 2 h and peaking at 6 h. Increa sing concentrations (1-5 mM) of xylitol and dihydroxyacetone in the pr esence of 5 mM glucose are also able to induce S14 and FAS gene expres sion progressively. Among the various glucose metabolites measured, gl ucose 6-phosphate, in contrast with xylulose 5-phosphate and metabolit es of the lower part of glycolysis, is the only one that shows a clear -cut parallelism between its concentration and the degree of S14 and F AS gene expression. We conclude that glucose 6-phosphate is the most l ikely signal metabolite for the glucose-induced transcription of this group of genes.