Upregulation of hepatic glucose 6-phosphatase gene expression in rats treated with an inhibitor of glucose-6-phosphate translocase

The multicomponent hepatic glucose 6-phosphatase (Glc-6-Pase) system cataly zes the terminal step of hepatic glucose production and plays a key role in the regulation of blood glucose. We used the chlorogenic acid derivative S 3483, a reversible inhibitor of the glucose-6-phosphate (Glc-6-P) transloc ase component, to demonstrate for the first time upregulation of Glc-6-Pase expression in rat liver in vivo after inhibition of Glc-6-P translocase. I n accordance with its mode of action, S 3483-treatment of overnight-fasted rats induced hypoglycemia and increased blood lactate, hepatic Glc-6-P, and glycogen. The metabolic changes were accompanied by rapid and marked incre ases in Glc-6-Pase mRNA (above 35-fold), protein (about 2-fold), and enzyma tic activity (about 2-fold). Maximal mRNA levels were reached after 4 h of treatment. Glycemia, blood lactate, and Glc-6-Pase mRNA levels returned to control values, whereas Glc-6-P and glycogen levels decreased but were stil l elevated 2 h after S 3483 withdrawal. The capacity for Glc-6-P influx was only marginally increased after 8.5 h of treatment. Prevention of hypoglyc emia by euglycemic clamp did not abolish the increase in Glc-6-Pase mRNA in duced by S 3483 treatment. A similar pattern of hypoglycemia and possibly o f associated counterregulatory responses elicited by treatment with the pho sphoenol- pyruvate carboxykinase inhibitor 8-mercaptopicolinic acid could a ccount for only a 2-fold induction of Glc-6-Pase mRNA, These findings sugge st that the significant upregulation of Glc-6-Pase gene expression observed after treatment of rats in vivo with an inhibitor of Glc-6-P translocase i s caused predominantly either by S 3483 per se or by the compound-induced c hanges of intracellular carbohydrate metabolism. (C) 2000 Academic Press.