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 catalyzes 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) translocase 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. In 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 increases in Glc-6-Pase mRNA (above 35-fold), protein (about 2-fold), and enzymatic 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 still 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 hypoglycemia by euglycemic clamp did not abolish the increase in Glc-6-Pase mRNA induced by S 3483 treatment. A similar pattern of hypoglycemia and possibly of associated counterregulatory responses elicited by treatment with the phosphoenolpyruvate carboxykinase inhibitor 3-mercaptopicolinic acid could account for only a 2-fold induction of Glc-6-Pase mRNA. These findings suggest 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 is caused predominantly either by S 3483 per se or by the compound-induced changes of intracellular carbohydrate metabolism.
Simon
C
C
Hoechst Marion Roussel Deutschland GmbH, Frankfurt am Main, 65926, Germany.
Herling
A W
AW
Preibisch
G
G
Burger
H J
HJ
D000818:Animals; D017920:Antiporters; D001786:Blood Glucose / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015309:Glucose Clamp Technique; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis / Q000235:genetics*; D007003:Hypoglycemia / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009004:Monosaccharide Transport Proteins; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D010848:Picolinic Acids / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
D017920:Antiporters; D001786:Blood Glucose; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D009004:Monosaccharide Transport Proteins; D010848:Picolinic Acids; D012333:RNA, Messenger; C113180:S 3483; C503533:Slc37a4 protein, rat; C111261:glucose 6-phosphate(transporter); C008363:3-mercaptopicolinic acid; D010770:Phosphotransferases; D005952:Glucose-6-Phosphatase