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A more recent version of this article appeared on July 6, 2001
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M101223200v1
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Papers In Press, published online ahead of print May 9, 2001
J. Biol. Chem, 10.1074/jbc.M101223200
Submitted on February 8, 2001
Revised on April 18, 2001
Accepted on May 9, 2001

Acute inhibition of hepatic glucose-6-phosphatase does not affect gluconeogenesis but directs gluconeogenic flux towards 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

Laboratory of Pediatrics, University Hospital Groningen, Groningen 9700RB

Corresponding Author: d.j.reijngoud{at}med.rug.nl

Effects of acute inhibition of glucose-6-phosphatase (G6Pase) activity by the chlorogenic acid derivative S4048 on hepatic carbohydrate fluxes was 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 (G6P) 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/kg.min; 8h) G6P 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 G6P was unaffected, i.e. 33.3 ± 2.0 vs. 33.2 ± 2.9 mu mole/kg.min in control and S4048-treated rats, respectively. Newly synthesized G6P was redistributed from glucose production (62 ± 1 % vs 38 ± 1 %; p<0.001) to glycogen synthesis (35 ± 5 % vs 65 ± 5 %; p<0.005) by S4048. This was associated with a strong inhibition (-82%) of the flux through glucokinase (GK), an increase (+83%) of the flux through glycogen synthase (GS) while the flux through glycogen phosphorylase (GP) remained unaffected. In livers from S4048-treated rats mRNA levels of genes encoding G6P hydrolase (~ 9-fold), G6P translocase (~ 4-fold), GS (~ 7-fold) and L-type pyruvate kinase (~ 4-fold) were increased, whereas GK 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 G6Pase activity by S4048 elicited: 1) a re-partitioning of newly synthesized G6P from glucose production into glycogen synthesis without affecting the gluconeogenic flux to G6P, 2) a cellular response aimed at maintaining cellular G6P homeostasis.


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