Transcriptional Glucose Signaling through The Glucose Response Element Is Mediated by the Pentose Phosphate Pathway

Abstract

Glucose catabolism induces the expression of the Ltype pyruvate kinase (L-PK) gene through the glucose response element (GIRE). The metabolic pathway used by glucose after its phosphorylation to glucose 6-phosphate by glucokinase to induce L-PK gene expression in hepatocytes remains unknown. The sugar alcohol xylitol is metabolized to xylulose 5-phosphate, an intermediate of the nonoxidative branch of the pentose phosphate pathway. In this study, we demonstrated that xylitol at low concentration (O.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 glucose 6-phosphate significantly. The effect of xylitol on the induction of the L-PK gene expression was noncumulative with that of glucose since 20 mM glucose plus 5 mM xylitol induced the expression of the L-PK/ CAT construct similarly to 20 mM glucose alone. In hepatocytes in primary 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 assumed 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-phosphate.

Role of glucose-6-phosphate and xylulose-5-phosphate in the regulation of glucose-stimulated gene expression in the pancreatic β cell line, INS-1E

“…Moreover, xylitol induces the expression of ChREBP target genes such as Pklr, S14 and Fasn in rat primary hepatocytes [33,34]. Thus, X5P is a glucose signal regulating the expression of glucose and lipid metabolism genes in the liver.…”

“…In primary hepatocytes, xylitol is converted into X5P by XYLB, and X5P enters the non-oxidative branch of the pentose phosphate pathway [31][32][33][34]. Moreover, xylitol induces the expression of ChREBP target genes such as Pklr, S14 and Fasn in rat primary hepatocytes [33,34].…”

Modulation of glucose responsiveness of insulinoma β-cells by graded overexpression of glucokinase

“…The fact that forced expression of glucokinase resulted in an enhancement of these responses adds further support for a link between them and the rate of glucose metabolism. Signaling for L-type pyruvate kinase gene induction might be mediated by the accumulation of the pentose phosphate pathway intermediate xylulose 5-phosphate (27). Distally, this intermediate appears to activate a specific protein phosphatase (30) and could hypothetically regulate the activity of a factor or cofactor of transcription directly or indirectly.…”

“…The L-type pyruvate kinase gene is transcriptionally induced in response to a rise of the extracellular glucose concentration in the endocrine ␤-cell (14) and in hepatocytes (26). Although the signaling mechanism remains incompletely understood, recent studies with hepatoma cells have suggested that the intermediate xylulose 5-phosphate, generated in the pentose phosphate pathway, was a critical metabolite of glucose for the pyruvate kinase gene response (27). The availability of the INS-r3-GK27 cell line allowed us to test the hypothesis that discrete increments in glucokinase activity would allow to amplify the pyruvate kinase gene response to an elevation of extracellular glucose.…”

Regulation of gene expression by glucose

“…Moreover, in vivo, the kinetics of hexose phosphate concentration fit with the time-related pattern of FAS gene induction. It must be pointed out that Doiron et al (1996) have proposed that xylulose-5-phosphate, a metabolite belonging to the pentose-phosphate pathway, is the signal metabolite. The involvment of one or the other metabolite thus awaits confirmation.…”