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J. Biol. Chem., Vol. 276, Issue 28, 25727-25735, July 13, 2001

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Acute Inhibition of Hepatic Glucose-6-phosphatase Does Not Affect Gluconeogenesis but Directs Gluconeogenic Flux toward Glycogen in Fasted Rats
A PHARMACOLOGICAL STUDY WITH THE CHLOROGENIC ACID DERIVATIVE S4048^*

Theo H. van Dijk, Fjodor H. van der Sluijs, Coen H. Wiegman, Julius F. W. Baller, Lori A. Gustafson^§, Hans-Joerg Burger^¶, Andreas W. Herling^¶, Folkert Kuipers, Alfred J. Meijer^§, and Dirk-Jan Reijngoud

From the  Laboratory of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Hospital Groningen, Groningen 9700 RB, The Netherlands, the ^§ Department of Biochemistry, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands, and ^¶ Aventis Pharma Deutschland GmbH, Frankfurt aM 65926, Germany

Effects of acute inhibition of glucose-6-phosphatase activity by the chlorogenic acid derivative S4048 on hepatic carbohydrate fluxes were examined in isolated rat hepatocytes and in vivo in rats. Fluxes were calculated using tracer dilution techniques and mass isotopomer distribution analysis in plasma glucose and urinary paracetamol-glucuronide after infusion of [U-¹³C]glucose, [2-¹³C]glycerol, [1-²H]galactose, and paracetamol. In hepatocytes, glucose-6-phosphate (Glc-6-P) content, net glycogen synthesis, and lactate production from glucose and dihydroxyacetone increased strongly in the presence of S4048 (10 µM). In livers of S4048-treated rats (0.5 mg kg¹ min¹; 8 h) Glc-6-P content increased strongly (+440%), and massive glycogen accumulation (+1260%) was observed in periportal areas. Total glucose production was diminished by 50%. The gluconeogenic flux to Glc-6-P was unaffected (i.e. 33.3 ± 2.0 versus 33.2 ± 2.9 µmol kg¹ min¹ in control and S4048-treated rats, respectively). Newly synthesized Glc-6-P was redistributed from glucose production (62 ± 1 versus 38 ± 1%; p < 0.001) to glycogen synthesis (35 ± 5% versus 65 ± 5%; p < 0.005) by S4048. This was associated with a strong inhibition (82%) of the flux through glucokinase and an increase (+83%) of the flux through glycogen synthase, while the flux through glycogen phosphorylase remained unaffected. In livers from S4048-treated rats, mRNA levels of genes encoding Glc-6-P hydrolase (~9-fold), Glc-6-P translocase (~4-fold), glycogen synthase (~7-fold) and L-type pyruvate kinase (~ 4-fold) were increased, whereas glucokinase expression was almost abolished. In accordance with unaltered gluconeogenic flux, expression of the gene encoding phosphoenolpyruvate carboxykinase was unaffected in the S4048-treated rats. Thus, acute inhibition of glucose-6-phosphatase activity by S4048 elicited 1) a repartitioning of newly synthesized Glc-6-P from glucose production into glycogen synthesis without affecting the gluconeogenic flux to Glc-6-P and 2) a cellular response aimed at maintaining cellular Glc-6-P homeostasis.

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