The rates of glycogen synthesis and glycogenolysis in the liver are mainly controlled by the phosphorylation state of glycogen synthase and phosphorylase, respectively(1) . In the fed state, there is a tight, inverse coupling between the activation states of the two enzymes(1, 2) . A key element in this control is the potent allosteric inhibition that phosphorylase a (phosphoenzyme) exerts on the hepatic glycogen-associated glycogen-synthase phosphatase (protein phosphatase 1G), which converts glycogen synthase b to the a form(1, 3, 4, 5) . This mechanism appears to explain the sequential inactivation of phosphorylase and activation of glycogen synthase in the liver after the administration of glucose(2) : binding of glucose to phosphorylase a renders the enzyme a better substrate for phosphorylase phosphatase; the conversion of phosphorylase a to b switches off glycogenolysis and relieves glycogen-synthase phosphatase from inhibition by phosphorylase a, thus allowing the phosphatase to activate glycogen synthase. Hence, little or no ``glycogen cycling'' (Glc-1-P glycogen Glc-1-P) is observed during glucose-induced hepatic glycogen synthesis in man (6) and during glycogen synthesis and subsequent glycogenolysis in cultured rat hepatocytes(7) .

A minimal concentration of glycogen is required for the inhibition of glycogen-synthase phosphatase by phosphorylase a(8) . Depletion of glycogen explains the anomalous situation in the liver of the fasted animal, which contains appreciable amounts of both phosphorylase a and glycogen synthase a, obviously without net glycogen synthesis(9, 10, 11) . However, the question then arises whether the absence of net glycogen synthesis reflects a full-blown substrate cycle or whether the synthase a measured in such liver homogenates is not catalytically active in the hepatocyte. Part of the present work was aimed at solving this dilemma, which has been a tantalizing problem for many years.

Our proposal (1, 2) that the mere removal of phosphorylase a would explain the glucose-induced activation of glycogen synthase has been challenged by Carabaza et al.(12) in a study on the effects of glucose analogues on isolated hepatocytes: while high concentrations of several analogues (e.g. 50 mM 6-deoxyglucose) promoted the inactivation of phosphorylase, only glucose, 5-thioglucose, and 2-deoxyglucose, which can be phosphorylated on carbon 6, were also able to activate glycogen synthase. More recently, while exploring the glycogenic action of 5-iodotubercidin, we also concluded that the activation of glycogen synthase could not be explained merely by the inactivation of phosphorylase(13) . Another part of the present work deals with the question of whether phosphorylation of glucose is essential for the glucose-induced activation of glycogen synthase.

EXPERIMENTAL PROCEDURES

Animals, Liver Cells, and Liver Preparations

Hepatocytes were prepared in the morning from the livers of male, overnight-fasted Wistar rats weighing 250 g(14) . The cells (5 10/ml) were incubated at 37 °C as described (14) in a Krebs-Henseleit medium supplemented with 13.5 mM lactate, 1.5 mM pyruvate, 0.2 mM glycerol, and (unless indicated otherwise) 10 mM glucose. Samples for the assays of glycogen synthase and phosphorylase were transferred into tubes containing an ice-cold buffer with inhibitors of protein kinases and phosphatases and were immediately frozen in liquid nitrogen(14) . Samples for glycogen determination were mixed with KOH (1 M final concentration), heated for 20 min at 90 °C, and neutralized with acetic acid. For the assay of Glc-6-P, the cells were separated from the incubation medium by centrifugation for 5 s at 10,000 g and deproteinized with cold 1 M HClO, and the mixture was centrifuged. The supernatant was neutralized with KOH and KHCO and clarified by centrifugation.

Glucose uptake by hepatocytes was measured in hepatocyte suspensions incubated at 20 °C with or without 10 mM glucose analogue for 5 min before the addition of 10 mM [U-C]glucose. After 1 and 5 min, aliquots were deposited in microcentrifuge tubes on a layer of ice-cold 0.15 M NaCl containing 50 mM glucose, and the hepatocytes were pelleted at once by centrifugation as described above and frozen in liquid N until deproteinization and determination of radioactivity.

For the preparation of gel-filtered liver extracts, fed rats were injected intraperitoneally with 70 µg of glucagon 10 min before decapitation to activate phosphorylase fully and to inactivate glycogen synthase. Their livers were homogenized in a Potter-Elvehjem tube in 3 volumes of an ice-cold solution containing 0.25 M sucrose, 50 mM glycylglycine, pH 7.4, and 1 mM dithiothreitol. The homogenate was centrifuged for 10 min at 8000 g, and 2.5 ml of supernatant (liver extract) was filtered in the cold as recommended by the manufacturer (Pharmacia Biotech Inc.) through a Sephadex G-25 column (10 1.5 cm) equilibrated with 50 mM glycylglycine, pH 7.4, and 1 mM dithiothreitol.

Assays

Results are means ± S.E. for the indicated number (n) of observations. Statistical differences were calculated with Student's t test for independent random samples and are considered as significant if p < 0.05.

F and P NMR Spectroscopies

Figure 1: F NMR spectra for synthetic F-Glc as such (A) and after incubation with hexokinase (B). A, H-decoupled spectrum for preparation I (2 mM). The insets with an expanded frequency scale show the F-F coupling (bottom) and imposed H-F couplings (top) in the H-coupled spectrum. B, spectrum for the same preparation (final concentration of 2 mM) after incubation for 4 h at 30 °C in 1.5 ml of 40 mM Tris, pH 7.8, containing 100 µg of hexokinase and 2.5 mM each ATP and magnesium acetate, and subsequent heating for 3 min at 90 °C. See ``Experimental Procedures'' and ``Results and Discussion'' for assignments of the numbered peaks.

Synthesis and Analysis of 2-Deoxy-2-fluoro--D-glucopyranosyl Fluoride

()

The H-decoupled F NMR spectra of both preparations were virtually identical. As illustrated in Fig. 1A for preparation I, the spectra contained two major doublets of equal intensity (doublets 2 and 3, centered at -72.02 and -125.70 ppm, respectively), which accounted for 82 and 83% of the total F signal in preparations I and II, respectively. These ratios were independent of the degree of saturation, tested at repetition times ranging between 1 and 5 s. The chemical shift values, F-F coupling constants (19.7 Hz), and the H-coupled spectra allow us to identify doublets 2 and 3 as the F-1 and F-2 signals, respectively, of F-Glc(19) . The glucosidic bond of F-Glc was acid-labile; after boiling for 10 min in 1 M HClO, 39% of the compound had been converted to 2-deoxy-2-fluoroglucose, with equivalent production of inorganic fluoride (data not shown).

An unidentified impurity gave rise to two minor doublets (Fig. 1A; doublets 1 and 4, centered at -65.54 and -130.77 ppm, respectively) of equal intensity and reciprocal F-F coupling (18 Hz), which amounted to 18% of the total F signal. The spectral parameters differ from those reported for the -anomer of F-Glc and for both anomers of F-mannose(19) .

Other Materials

RESULTS AND DISCUSSION

Activities of Phosphorylase and Glycogen Synthase in Fasted Mouse Liver

Figure 2: Levels of phosphorylase a and glycogen synthase a in the livers of overnight-fasted, anesthetized mice injected with saline () or glucose (). The mice were injected via a tail vein either with glucose (1 mg/g of body weight) or with an equivalent volume of saline 5 min before part of the liver was quick-frozen in situ between aluminium tongs cooled in liquid N. The hatchedarea covers the results obtained previously with 120 fed mice injected for various times with saline, glucose, or glucagon, as shown individually in Fig. 3of (2) .

Figure 3: Effects of glucose and F-Glc on the inactivation of phosphorylase and on the activation of glycogen synthase in a gel-filtered liver extract. A gel-filtered liver extract, prepared as described under ``Experimental Procedures,'' was incubated at 25 °C in the presence of 10 mM (NH)SO only () or plus 10 mM glucose () or 0.6 mM F-Glc (▴). At the indicated times, samples were taken for the assays of phosphorylase and glycogen synthase.

Adopted Strategy

The major problem with the glucose analogues that have been tested biologically (12) is their poor efficiency, as reflected by their low affinity for phosphorylase(21, 22) . Better candidates emerged from a study by Street et al.(22) of deoxyfluoro derivatives of glucose, which yielded several compounds that were superior to glucose as inhibitors of phosphorylase (at least the b form from skeletal muscle). One such compound is -D-glucopyranosyl fluoride(22) , which had to be rejected because it is a good substrate for -1,4-glucosidases as well as for amylo-1,6-glucosidase(23, 24) ; obviously, we could not tolerate intracellular production of fluoride, which is a potent inhibitor of, for example, protein phosphatases(25) . Another good inhibitor of phosphorylase, 2-deoxy-2-fluoroglucose, can be phosphorylated on carbon 6 and further metabolized beyond the UDP-sugar stage(26) . Hence, we decided to explore the double-fluorinated derivative F-Glc, which was also the most potent phosphorylase inhibitor synthesized(22) , with a Kof 0.2 mM for muscle phosphorylase b, i.e. 10 times better than glucose.

F-Glc Is Metabolically Inert

A quantitative comparison conducted at a much lower concentration of hexokinase indicated, however, that F-Glc was phosphorylated at least 5000-fold more slowly than glucose. This finding agrees with that of Bessell et al.(28) , who found that 2-deoxy-2-fluoroglucose was a good substrate for hexokinase, whereas -D-glucopyranosyl fluoride was neither a substrate nor an inhibitor.

Subsequent work indicated that F-Glc (10 mM) was neither phosphorylated nor defluorinated when incubated with hepatocytes. For this purpose, we analyzed the F spectra of neutralized HClO extracts of both the cell pellet and the medium after incubation of hepatocytes with F-Glc for up to 4 h (data not shown). Neither F-Glc-6-P nor inorganic fluoride could be detected. The former observation is in agreement with the absence of hexokinase (and the presence of the more specific glucokinase) in differentiated hepatocytes(29) . Clearly, F-Glc is not a substrate for hepatic -glucosidases; it has been reported as an inhibitor of yeast -glucosidase(23) .

We have checked that F-Glc did not measurably interfere with the transport and phosphorylation of glucose. Preincubation of hepatocytes for 5 min with 10 mM F-Glc influenced neither the uptake of 10 mM glucose by hepatocytes (measured after 1 and 5 min at 20 °C) nor the intracellular concentration of Glc-6-P during incubation at 37 °C with 10 or 50 mM glucose for up to 10 min (data not shown).

Effects of F-Glc in Gel-filtered Liver Extracts

This suggests that liver phosphorylase a has a much higher affinity for F-Glc than for glucose, as experimentally confirmed (Fig. 4): 1 mM F-Glc sufficed to achieve 50% inactivation of phosphorylase after 3 min of incubation, whereas 20 mM glucose was required to achieve the same effect.

Figure 4: Effect of the concentrations of glucose and F-Glc on the inactivation of phosphorylase in gel-filtered liver extracts. A gel-filtered liver extract was prepared and incubated as described in the legend to Fig. 3with the indicated concentrations of either glucose or F-Glc. After 3 min, a sample was taken for the assay of phosphorylase. Results are the means ± S.E. for five liver preparations.

Effects of F-Glc on Phosphorylase and Glycogen Synthase in Isolated Hepatocytes

Figure 5: Effects of glucose and F-Glc on the activation states of phosphorylase and glycogen synthase in hepatocytes isolated from fasted rats. Freshly isolated hepatocytes were incubated in the presence of the indicated concentrations of glucose only (, ) or plus the indicated concentrations of F-Glc (, ▴). At the times shown, samples were taken for the assays of phosphorylase (--) and glycogen synthase(- - - ). Results are the means ± S.E. for five to eight hepatocyte preparations.

Taken together, the data in Fig. 5(B and C) illustrate clear discrepancies between the extent of inactivation of phosphorylase and the extent of activation of glycogen synthase. They are compatible with a (partial) inactivation of phosphorylase as a prerequisite for the activation of glycogen synthase, but they show that the mere inactivation of phosphorylase is not sufficient to elicit the activation of glycogen synthase. This conclusion, based on the use of a superior glucose analogue, corroborates the proposal of Carabaza et al.(12) , who were limited by the choice of 1-deoxyglucose and 6-deoxyglucose as nonphosphorylatable glucose analogues. In comparison with glucose, 1-deoxyglucose binds to phosphorylase with some 4-fold lower affinity(21, 22) , while 6-deoxyglucose is a very poor ligand(22) . In our hands, 50 mM 1-deoxyglucose decreased the concentration of phosphorylase a in hepatocytes by only 25%, and 50 mM 6-deoxyglucose was ineffective (data not shown).

Activation of Glycogen Synthase May Require a Rise in Glc-6-P

Figure 6: Effect of the glucose concentration on the intracellular concentration of Glc-6-P in hepatocytes incubated in the presence of F-Glc. Freshly isolated hepatocytes were incubated in the presence of either 10 mM glucose plus 10 mM F-Glc (; cf.Fig. 5B) or 50 mM glucose plus 5 mM F-Glc (▴; cf.Fig. 5C). At the indicated times, samples were taken for the determination of the intracellular concentration of Glc-6-P. Results are the means ± S.E. for four to five hepatocyte preparations.

First, some glucose derivatives that are phosphorylated on carbon 6 but not further metabolized have been shown to elicit the activation of glycogen synthase (besides inactivation of phosphorylase). This was initially discovered in studies on polymorphonuclear leukocytes, where an extensive and long-lasting activation of glycogen synthase could be elicited by the addition of 0.5-1 mM 2-deoxyglucose (32) or glucosamine(33) . Similar results were obtained more recently upon incubation of hepatocytes with 2-deoxyglucose and 5-thioglucose(12) .

Second, Glc-6-P is a well known ligand of glycogen synthase, and binding could alter the enzyme conformation so as to expose phosphorylated site(s) to the action of protein phosphatases or to shield such site(s) from synthase kinases. There is in fact evidence in vitro that the addition of Glc-6-P can enhance the dephosphorylation and activation of purified (muscle) glycogen synthase by the catalytic subunits of protein phosphatases 1 and 2A(34) . However, Glc-6-P had also been shown many years ago to block in a crude liver extract the inactivation of glycogen synthase elicited by MgATP plus cAMP(35) . The mechanism has recently been investigated with purified muscle glycogen synthase(36) . The inhibition is limited to the action of cAMP-dependent protein kinase on glycogen synthase, but at least in vitro, it operates at physiological concentrations of Glc-6-P.

Further work will obviously be required to delineate the importance of Glc-6-P in the activation of glycogen synthase and the relative importance of synthase phosphatases and synthase kinases in substrate-directed effects of Glc-6-P. To explore these issues, we plan to test on isolated hepatocytes a series of newly synthesized glucose analogues (37) in combination with inhibitors of protein kinases and protein phosphatases(13, 38) .

Evidence for a Substrate Cycle in Hepatocytes from Fasted Rats

For the sake of comparison, other glycogenic agents (50 mM glucose, 0.1 mM Proglycosyn) have also been used, alone and in combination (Table 1). Proglycosyn is a phenylacyl imidazolium compound that causes the inactivation of phosphorylase and (in contrast to F-Glc) also the activation of glycogen synthase (Table 1)(39, 40) . Intracellular glucuronidation of Proglycosyn is an essential step in the generation of the active compound(40) , whose action mechanism remains currently unknown. Using these various agents, a wide range of values for glycogen accumulation was obtained, and the actual rates of glycogen synthesis have been compared with the concurrent levels of glycogen synthase a (Fig. 7). In this graph, a line has been drawn from the origin to the result obtained with 50 mM glucose plus 5 mM F-Glc plus 0.1 mM Proglycosyn, yielding the highest rate of glycogen accumulation, elicited by 89% synthase a and with barely 5% phosphorylase a. Results significantly below this line would indicate that either synthase a is catalytically less efficient than expected or that glycogen is being degraded simultaneously. One observes a clear deviation only in the few instances where 15% or more of phosphorylase was present in the a form and most prominently in the cells incubated in the presence of 10 mM glucose only. Fig. 7shows that the addition of 5 and 10 mM F-Glc to the latter cells caused an almost purely upward movement of the experimental result, i.e. net glycogen deposition occurred as a result of a selective inactivation of phosphorylase; one notices also that, in the presence of 10 mM each glucose and F-Glc (10.5% phosphorylase a), the substrate cycle had largely been suppressed. In fact, the data in Fig. 7allow us to calculate (since 1 g of hepatocytes contains 220 mg of protein) that the cells incubated with 10 mM glucose only should have synthesized 230 nmol of glycogen/min/g (wet weight) in the absence of substrate cycling. Since the actual rate of glycogen accumulation was merely 50 nmol/min/g, the cycling must have consumed 180 nmol of ATP/min/g. Upon addition of 10 mM F-Glc, the rate of glycogen accumulation rose to 210 nmol/min/g, while the cycling decreased to 60 nmol of ATP/min/g. In conclusion, our data indicate that, in the liver of the fasted animal (Fig. 2), glycogen synthase a is indeed fully active and that the absence of net glycogen accumulation is due to continuous glycogenolysis by phosphorylase a.

Figure 7: Comparison between the concentration of glycogen synthase a and the rate of glycogen synthesis in hepatocytes isolated from fasted rats. Freshly isolated hepatocytes were incubated in the presence of 10 mM glucose (opensymbols) or 50 mM glucose (closedsymbols), either as such (, ) or in the presence of F-Glc (5 mM (, ▴) and 10 mM ()), 0.1 mM Proglycosyn (PGS; , ▾), or 5 mM F-Glc plus 0.1 mM Proglycosyn (both; ▪). The rate of glycogen synthesis is plotted as a function of the activation state of glycogen synthase (data from Table 1). Horizontal and verticalbars represent ±S.E. Values to the left or right of the horizontalbars represent the mean value for phosphorylase a as a percent of the total (±S.E. is indicated in Table 1).

FOOTNOTES

*

This work was supported in part by Belgian Fund for Medical Scientific Research Grant 3.0119.94 and by European Union Human Capital and Mobility Contract CHRX-CT93-0242. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

Recipient of a fellowship granted by the Scientific and Technological Cooperation between Quebec and Flanders. On leave from the Laboratoire d'Endocrinologie Métabolique, Departments of Nutrition and Biochemistry, University of Montreal, Montreal H3C 3J7, Canada. Present address: Div. of Endocrinology, Albert Einstein College of Medicine, Bronx, NY 10461.

¶

Deceased October 31, 1993.

**

To whom correspondence should be addressed: Afdeling Biochemie, KULeuven Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel.: 32-16-345700; Fax: 32-16-345995.

()

The abbreviation used is: F-Glc, 2-deoxy-2-fluoro--D-glucopyranosyl fluoride.

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