Glucocorticoids activate transcription of the gene for the glucose-6-phosphate transporter, deficient in glycogen storage disease type 1b

Deficiencies in the glucose-6-phosphate transporter (G6PT) cause glycogen s torage disease type 1b (GSD-1b), a heritable metabolic disorder. The G6PT p rotein translocates glucose-6-phosphate from the cytoplasm to the lumen of the endoplasmic reticulum, where glucose-6-phosphatase metabolizes it to gl ucose and phosphate. Therefore, G6PT and glucose-6-phosphatase work in conc ert to maintain glucose homeostasis. To delineate the control of G6PT gene expression, we first demonstrated that transcription of the gene requires h epatocyte nuclear factor la. Consequently, hepatocyte nuclear factor la-nul l mice manifest a G6PT deficiency like that of GSD-1b patients. In this stu dy, we delineated the role of glucocorticoids in the transcription of the G 6PT gene. We showed that the basal G6PT promoter is contained within nucleo tides -369 to -1 upstream of the translation start site, which contains thr ee activation elements. Further, we demonstrated that glucocorticoids activ ate G6PT transcription and that glucocorticoid action is mediated through a glucocorticoid response element within activation element-2 of the promote r. Taken together, the results suggest that glucocorticoids play a pivotal role in regulating the G6PT gene.