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Department of Biochemistry, Molecular Biology and Biophysics (C.W., A.K.S., L.-J.P., A.H.H., J.E.H., H.C.T., A.J.L.), Medical School, University of Minnesota, Minneapolis, Minnesota 55455; and Veterans Administration Medical Center (D.A.O.), Minneapolis, Minnesota 55417
Address all correspondence and requests for reprints to: Alex J. Lange, Department of Biochemistry, Molecular Biology and Biophysics, Medical School, University of Minnesota, 6–155 Jackson Hall, 321 Church Street SE, Minneapolis, Minnesota 55455. E-mail: lange024{at}umn.edu.
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protein, a transcription factor involved in G-6-Pase gene expression. In conclusion, F-2,6-P2 can stimulate hepatic GK gene expression in an insulin-independent manner and can secondarily affect G-6-Pase gene expression by lowering the level of plasma glucose. |
Introduction |
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Hepatic GK gene expression is induced by insulin and repressed by glucagon (7, 8, 9). Induction of GK gene expression by insulin requires insulin signaling through phosphatidylinositol 3-kinase (PI3-K) to protein kinase B (Akt) (9). Furthermore, activation (phosphorylation) of Akt results in an induction of GK gene expression similar to that induced by insulin (9). Because insulin and glucagon have effects on sterol regulatory element binding protein 1c (SREBP-1c) nuclear activity similar to those on GK gene expression liver, Foretz et al. (10) suggested that this insulin-regulated transcription factor is involved in hepatic GK gene expression. In isolated hepatocytes or livers of streptozotocin (STZ)-treated mice, overexpression of SREBP-1c bypassed the requirement of insulin for GK gene expression (10, 11, 12). Conversely, overexpression of the dominant negative SREBP-1c blocked the effect of insulin on induction of GK expression (10). Thus, SREBP-1c may serve as a mediator of the effect of insulin on induction of GK gene expression. However, it is unclear whether SREBP-1c is a downstream target of Akt signaling for the induction of hepatic GK gene expression, even though acute activation of Akt is sufficient to induce SREBP1c mRNA accumulation in primary hepatocytes (13). In contrast to hepatic GK gene expression, G-6-Pase gene expression is suppressed by insulin and paradoxically stimulated by glucose (14, 15). Insulin has a dominant suppressive effect on G-6-Pase gene expression acting via a proximal negative insulin response element (14, 16). This element has then been designated as an insulin response unit consisting of region A and region B (16, 17, 18, 19). Hepatic nuclear factor-1 (HNF-1) can bind region A, serving as an accessory factor that is required for the repression of G-6-Pase gene transcription by insulin (17).
Fructose-2,6-bisphosphate (F-2,6-P2) was identified as an allosteric activator of the glycolytic enzyme 6-phosphofructo-1-kinase (6PF-1-K) and an inhibitor of the gluconeogenic enzyme fructose-1,6-bisphosphatase (F-1,6-P2ase) (20, 21, 22, 23). Increasing the hepatic content of F-2,6-P2 suppresses HGP and lowers the levels of plasma glucose in mouse models of diabetes (6, 24). The mechanism for the effect of F-2,6-P2 on suppression of HGP was originally proposed to be due to activation of glycolysis and inhibition of gluconeogenesis (24, 25). Indeed, increasing hepatic glycolysis by high F-2,6-P2 was verified by the increased production of lactate and pyruvate (24). Because GK activity is a prerequisite for glycolysis in the liver (26), an up-regulation of hepatic GK would be necessary to increase glycolysis in STZ-treated animals, where GK and glycolytic flux are very low due to the absence of insulin (7, 26, 27). We therefore postulated that high levels of F-2,6-P2 could restore GK gene expression in the absence of insulin. In the present study, we used STZ-treated 129J mice as a diabetic model to eliminate any effect of insulin on hepatic gene expression and investigated the gene expression of hepatic GK and G-6-Pase in response to F-2,6-P2 elevation via adenovirus-mediated overexpression of a bisphosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PF-2-K/F-2,6-P2ase). This model allows us to separate high F-2,6-P2 effects from insulin-mediated effects. A possible mechanism for this effect on GK gene expression is discussed.
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Materials and Methods |
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Animal experiments
Male 129J mice were 10–12 wk old and obtained from The Jackson Laboratory (Bar Harbor, ME). Type 1 diabetes was induced by STZ treatment (a single ip injection at a dose of 3.5 mg/20 g body weight at d -7). Five days later (d -2), all STZ-treated mice were confirmed to be diabetic by plasma glucose levels higher than 400 mg/dl. Adenovirus or recombinant insulin was administrated to diabetic mice at d 0 or d 7, respectively. All mice were fed ad libitum. Before collection of blood and liver samples, mice were fasted for 4–6 h.
Animal experiments included three protocols. Protocol A (effect of high F-2,6-P2 levels): this protocol was designed to analyze the changes in hepatic gene expression of GK and G-6-Pase upon increasing hepatic content of F-2,6-P2. All treatments in this protocol were the same as previously described (24). Briefly, nineteen mice were divided into four groups (four to six in each group): saline-injected control mice, and STZ-induced diabetic mice treated with Ad-gal, Ad-Bif-WT, or Ad-Bif-BPD. The diabetic mice were infused with adenovirus at d 0 and followed for 7 d. The levels of plasma glucose were monitored just before the animals were killed, using an affinity glucose assay kit from Sigma-Aldrich Co. (St. Louis, MO). After collection of blood samples, mice were killed by decapitation. The abdomen was quickly opened and liver samples were immediately freeze-clamped in liquid nitrogen and stored at -70 C for subsequent analyses. Protocol B (time course of F-2,6-P2 effect): this protocol was designed to determine the time course of the hepatic gene expression of GK and G-6-Pase in response to increased hepatic F-2,6-P2 content produced by adenovirus treatment. In this protocol, only Ad-Bif-BPD was used to treat STZ-induced diabetic mice. Blood and liver samples were collected at d 0, 0.5, 1, 1.5, 3, 5, or 7 (four to six per time point). Protocol C (insulin action): this protocol was designed to determine the effect of insulin on hepatic F-2,6-P2 content as it relates to hepatic GK gene expression. In this protocol, STZ-induced diabetic mice were treated with insulin (0.05 U/g body weight, Lantus, Aventis, MO) at d 7 (14 d after STZ treatment) for 0, 5 min, 30 min, 4 h, 8 h, or 24 h (four to six in each group). Because insulin stimulates hepatic GK gene expression at the protein level as early as 4 h post induction (7), a group of STZ-induced diabetic mice receiving Ad-Bif-KD (kinase deficient) infusion (on d 0) were treated with insulin for 4 h (at d 7) to determine the effect of insulin on stimulating hepatic GK gene expression in a state where F-2,6-P2 was maintained at a low level. Tissue samples were collected as described in protocol A.
All protocols were reviewed and approved by the Institutional Animal Care and Use Committees of the University of Minnesota.
Determination of hepatic content of F-2,6-P2 and lactate
F-2,6-P2 was extracted from fresh liver tissue at 80 C in 50 mM NaOH and measured using the 6PF-1-K activation method (24). Hepatic lactate concentration was assayed in liver homogenate as previously described (24).
Measurement of plasma insulin
Plasma insulin was measured by a rat insulin ELISA kit (Crystal Chem. Inc., Chicago, IL). Reactivity of the kit to mouse insulin is 105%. Mouse insulin was used as a standard.
RNA extraction and Northern blot analysis
Total RNA was extracted from fresh liver tissue with Stat-60 following the protocol of the manufacturer (Tel-Test B, Inc., Friendswood, TX). Northern blots were performed as previously described (24, 29). A total of 30 µg RNA was electrophoresed on a 1% formaldehyde-denatured agarose gel in 1x 3[N-morpholino]propanesulfonic acid buffer. The RNA was visualized with ethidium bromide and transferred to a GeneScreen membrane (DuPont, Boston, MA). A 0.9-kb cDNA of rat liver GK and a 1.4-kb cDNA of catalytic subunit of rat liver G-6-Pase were labeled with -32P-deoxy-CTP and used as probe for GK and G-6-Pase mRNA detection, respectively (24, 30).
Determination of changes in hepatic GK and G-6-Pase protein and activity
Liver homogenates and microsomes were prepared from frozen mouse liver as previously described (6, 24) for GK and G-6-Pase determinations, respectively. The concentration of extracted protein was measured by the BCA method (Pierce, Rockford, IL). For Western blots, equal amounts of total proteins were loaded for SDS-PAGE and transferred to an Immobilon P membrane (Millipore, Bedford, MA). Rabbit antirat liver GK or G-6-Pase serum were used as primary antibodies at a 1:1,000 dilution and was followed by a 1:10,000 dilution of goat antirabbit horseradish peroxidase-conjugated secondary antibody kit (ECL, Amersham Life Science, Buckinghamshire, UK). For enzyme activity determinations, the maximum velocity of GK was measured at 30 C using a coupled spectrophotometric assay with glucose-6-phosphate (G-6-P) dehydrogenase as the coupling enzyme (31) and the maximum velocity of G-6-Pase was assayed by the inorganic phosphate release method as described by Burchell et al. (32) and Lange et al. (33).
Determination of hepatic SREBP-1c gene expression
SREBP-1c was determined by the real-time PCR method as previously described (34). A total of 0.1 µg RNA was used for the determination. Results were normalized to a control transcript coding for the large ribosomal subunit protein RPL32.
Western blot analyses of insulin signaling proteins and HNF-1
Frozen livers were homogenized in the lysis buffer [50 mM HEPES (pH 7.4), 1% Triton X-100, 50 mM sodium pyrophosphate, 0.1 M sodium fluoride, 10 mM EDTA, 10 mM sodium orthovanadate, 10 µg/ml aprotinin, 10 µg/ml leupeptin, 2 mM benzamidine, and 2 mM phenylmethylsulfonyl fluoride] with a Janke & Kunkel homogenizer. Insulin signaling proteins [insulin receptor (IR), IR substrate-1 and -2 (IRS-1 and IRS-2), and Akt] were analyzed by Western blot as described by Michael et al. (35). Antibodies against IR, IRS-1, IRS-2, Akt, and phospho-Akt were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). HNF-1 was determined by Western blot as described above. Antibody against HNF-1 was also purchased from Santa Cruz Biotechnology.
Statistical analysis
All data are presented as means ± SE. Multiple comparisons were made by two-way ANOVA. Differences were considered significant if P < 0.05.
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). After Ad-Bif-WT or Ad-Bif-BPD treatment, overexpression of either wild-type or bisphosphatase-deficient 6PF-2-K/F-2,6-P2ase resulted in increases in hepatic F-2,6-P2 content (Table 1). In accord with our previous studies (24), the levels of plasma glucose were decreased and negatively correlated with increases in hepatic F-2,6-P2 levels. At d 7, hepatic GK activity was increased and G-6-Pase activity was decreased (Table 1), which is consistent with improved glucose homeostasis.
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, A and B). Also, these changes in the protein amount correspond with those of enzyme activity (Table 1
). After increasing hepatic F-2,6-P2 content, the GK gene expression was up-regulated at both the mRNA and protein level in the STZ-Ad-Bif-WT and the STZ-Ad-Bif-BPD groups, whereas G-6-Pase gene expression was down-regulated only in STZ-Ad-Bif-BPD group at both the mRNA and protein level (Fig. 1, A and B). Ad-Bif-BPD treatment resulted in a 13-fold increase in GK and a 2-fold decrease in G-6-Pase protein. Both changes were quantitatively significant (data not shown). Importantly, these changes occurred in the absence of insulin.
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). Concurrent with the increases in hepatic F-2,6-P2 content, hepatic lactate concentrations were increased (Fig. 2B), indicating increased glycolytic flux. Hepatic lactate concentrations increased further from d 3–7 (P < 0.05 vs. d 1.5). The levels of plasma glucose decreased steadily from d 3–7 in the STZ-Ad-Bif-BPD group (P < 0.05 vs. d 0, at d 3 and 5 and P < 0.01 vs. d 0, at d 7, Fig. 2C), whereas it remained the same from d -2 to 7 in the STZ-Ad-gal group. To compare the time sequence of changes in hepatic F-2,6-P2 content pertinent to changes in levels of hepatic lactate and plasma glucose, we normalized these three parameters to their maximal values at d 0 (glucose) or d 7 (F-2,6-P2 and lactate). As shown in Fig. 2D, increases in hepatic content of F-2,6-P2 and lactate preceded the decrease in levels of plasma glucose. This indicates that an increase in hepatic glycolysis promoted by elevated F-2,6-P2 levels may be the primary event for regulation of glucose homeostasis.
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). Although these data suggest that hepatic GK is necessary for lowering levels of plasma glucose in the context of the data in Fig. 2, they also suggest that the induction of GK gene expression was subsequent to the increase in F-2,6-P2 and glycolysis. On the other hand, the protein expression of hepatic G-6-Pase was down-regulated only after a decrease in levels of plasma glucose, starting from d 5 post Ad-Bif-BPD treatment (Fig. 3). Therefore, effects of F-2,6-P2 on hepatic G-6-Pase expression are most likely to be secondary to its effect on lowering level of plasma glucose, which is clearly different from that regulating hepatic GK expression. Changes in protein levels of both GK and G-6-Pase correlated with mRNA changes in preceding experiments (Fig. 1); therefore, we view the changes in the time course study with respect to protein level to indicate changes in gene expression.
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). Consistent with lacking insulin in STZ-treated mice, HNF-1, a transcription factor involved in G-6-Pase gene expression was decreased. The protein levels of HNF-1 were significantly increased in response to increasing hepatic F-2,6-P2 content (Fig. 4B).
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). For Protocol B (time course of F-2,6-P2 effect), increasing F-2,6-P2 content, again, led to phosphorylation of Akt in liver of diabetic mice lacking insulin, starting from 12 h post Ad-Bif-BPD treatment (Fig. 5B). The Akt phosphorylation paralleled increases in hepatic F-2,6-P2 content, preceding increases in GK protein. In addition, the greatest extent of the increase in phosphorylated Akt clearly resulted from the large dose bolus of insulin that was injected. It suggests that there may be at least two pathways through which insulin induces phosphorylation of Akt. One of the pathways can be modulated by changing the hepatic F-2,6-P2 content. The quantitative changes in Akt-phosphorylation upon increasing F-2,6-P2 content are reproducible and significant.
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). Hepatic F-2,6-P2 content was maximal at 4 h post insulin administration. Simultaneously, Akt phosphorylation was increased. Here, the greater extent of the increase in phosphorylated Akt obviously resulted from the bolus of insulin that was injected. Clearly, increases in hepatic GK protein lagged behind the increases in both hepatic F-2,6-P2 content and Akt phosphorylation. Because insulin-stimulated increases in GK mRNA do not appear within a hour after insulin treatment (7, 36), it is most likely that increases in hepatic GK mRNA also lagged behind increases in hepatic F-2,6-P2 content and Akt phosphorylation. Interestingly, insulin-induced Akt phosphorylation was partially blocked by preventing increases in hepatic content of F-2,6-P2 through overexpression of kinase-deficient 6PF-2-K/F-2,6-P2ase (Fig. 6B). This treatment also led to a partial stimulation of insulin on hepatic GK gene expression, presumably due to some impairment in Akt phosphorylation. Taken together, these observations indicate that F-2,6-P2 plays a key role in induction of hepatic GK gene expression by insulin.
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expression after restoration of GK. To understand the effects of F-2,6-P2 on insulin signaling, we investigated several key proteins in the insulin signaling pathway. Levels of IR, IRS-1, and IRS-2 protein were unchanged (data not shown). However, a downstream signaling molecule, Akt, was up-regulated both in protein amount and activity (phosphorylation at Ser473) in the livers of mice with high F-2,6-P2 content. The time course of changes in Akt phosphorylation paralleled increases in hepatic F-2,6-P2 content. Moreover, we observed that insulin increases hepatic F-2,6-P2 content rapidly and closely associated with Akt phosphorylation, which is established before the restoration of hepatic GK. These observations indicate that F-2,6-P2 level and Akt phosphorylation may play a role in insulin-stimulated GK gene expression. Two possible pathways for signaling by insulin and F-2,6-P2 can be postulated. In the first, insulin and F-2,6-P2 work through distinct upstream pathways that converge on a common point at (or above) the level of Akt. This hypothesis would provide two pathways that could influence Akt activation in animals experiencing increased insulin. This model is supported by the observation that F-2,6-P2 produces less effect on Akt phosphorylation than insulin does (quantitative data not shown). Furthermore, insulin is still able to induce some Akt phosphorylation in animals treated with Ad-Bif-KD, which prevents an increase in F-2,6-P2. Taken together, these results indicate that the F-2,6-P2 pathway is distinct from the well established insulin signaling pathway that activates Akt via IR (37). In the second model, F-2,6-P2 is an intermediate of the insulin signaling pathway for Akt activation and increased GK gene expression. In support of this model, insulin-induced Akt phosphorylation was partially blocked by preventing increases in F-2,6-P2 via overexpression of the kinase-deficient 6PF-2-K/F-2,6-P2ase and consequently, GK gene expression was only partially stimulated by insulin. Additionally, insulin was shown to increase F-2,6-P2 levels acutely in a manner consistent with this model.
In addition to insulin, glucose metabolism, by generating xylulose-5-phosphate and stimulating protein phosphatase (38), can also increase F-2,6-P2 content. This pathway depends on GK activity to initiate glucose metabolism, linking the insulin and glucose signaling arms of the pathway. These relationships are shown schematically in Fig. 7. Regardless of which pathway operates, the initial increases in F-2,6-P2 and/or a regulatory metabolite generated by F-2,6-P2-driven glycolysis activate a signaling cascade that activates Akt. Subsequently, the activation of Akt triggers a series of reactions, which may thereby permit a further increase F-2,6-P2 and/or glycolytic regulatory metabolite to bring about induction of GK gene expression. This mechanism may explain why GK gene expression continues to increase even after Akt phosphorylation has reached a relatively stable level upon increasing F-2,6-P2 content by either viral treatment or insulin administration (Figs. 4 and 5B). Thus, Akt phosphorylation may play the role of a trigger. Alternatively, phosphorylation of Akt synergistically effects unknown factors through a discrete pathway to facilitate GK gene expression. It should be pointed out that the turnover rates of Akt phosphorylation and GK gene expression are not necessarily the same. Thereby, it is possible that a delay in the accumulation of GK protein also contributes to the lag between events of signaling and gene expression. Regardless of mechanism, the effect of increasing F-2,6-P2 content on GK gene expression in the absence of insulin is fundamental because it establishes that insulin is not required for GK gene expression, as previously reported (7, 8, 9, 10). The effect of F-2,6-P2 is manifest in both the insulin-resistant (6) and insulin-deficient (STZ-treated) states, although the effects are more pronounced in the insulin-deficient state.
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Concomitant with effects of hypoinsulinemia, STZ-induced hyperglucagonemia represses hepatic GK gene expression (41). It has been proposed that a decrease in glucagon through derepression may also contribute to increases in hepatic GK gene expression. We did not measure changes in the levels of glucagon in the present study. Its contribution to the effect of F-2,6-P2 on hepatic GK may be minor because the increases we observed on GK mRNA are an order of magnitude greater than those produced by reducing hyperglucagonemia. In fact, hyperglucagonemia may serve to blunt the ability of the overexpression to raise F-2,6-P2 levels by promoting phosphorylation of endogenous 6PF-2-K/F-2,6-P2ase and thereby decreasing its kinase activity.
The decrease in G-6-Pase gene expression in the liver was the slowest event in our time course study. This change occurred only after achieving nearly normal levels of plasma glucose, indicating that glucose is the main regulator of G-6-Pase gene expression in liver. It is most likely that lowering of plasma glucose decreases its stimulatory effect on G-6-Pase gene expression (15). In addition, the role of G-6-Pase in the regulation of glycemia may not be as important as GK. The concentration of hepatic G-6-P, which is a possible intracellular metabolite mediating the glucose effect on G-6-Pase gene expression (42, 43), did not change upon increasing hepatic F-2,6-P2 content (data not shown), indicating that the decrease in G-6-Pase gene expression due to lower levels of glucose is not related to G-6-P concentration. Because HNF-1 plays a role in G-6-Pase gene expression (17) evidenced by HNF-1 null mice having increased hepatic G-6-Pase gene expression similar to that observed in diabetic animals (44), we determined HNF-1 protein levels upon increasing F-2,6-P2 content. Interestingly, an elevation in HNF-1 in protein was observed, which is likely involved in the down-regulation of G-6-Pase gene expression. The mechanism for increase in HNF-1 is unclear, but may be related to glucose metabolism. Clearly, increasing hepatic content of F-2,6-P2 affects hepatic G-6-Pase gene expression through an indirect pathway or a secondary mechanism that differs from its effect on hepatic GK through a more rapid direct mechanism involving an insulin signaling pathway. Again, we cannot rule out the possibility that changes in half-life of mRNA and protein amount of G-6-Pase are also achieved upon increasing hepatic F-2,6-P2 content.
In conclusion, we report the novel observation that hepatic GK gene expression may be restored by high F-2,6-P2, even in the absence of insulin. A signaling pathway may exist that mediates the effect of high F-2,6-P2 on the induction of hepatic GK gene expression. The restoration of hepatic GK is required for lowering levels of blood glucose, which subsequently decrease hepatic G-6-Pase gene expression. We also demonstrate that increased hepatic F-2,6-P2 modulates glucose metabolism in liver through its differential effects on GK and G-6-Pase gene expression in addition to its well established allosteric effect on 6PF-1-K.
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Abbreviations: Ad-gal, Virus containing Escherichia coli ß galactosidase; Bif, bifunctional enzyme; BPD, biphosphatase deficient; F-2,6-P2, fructose-2,6-bisphosphate; F-1,6-P2ase, fructose-1,6-bisphosphatase; GK, glucokinase; G-6-P, glucose-6-phosphate; G-6-Pase, glucose-6-phosphatase; HGP, hepatic glucose production; HNF, hepatic nuclear factor; IR, insulin receptor; IRS, IR substrate; KD, kinase deficient; 6PF-1-K, 6-phosphofructo-1-kinase; 6PF-2-K/F-2,6-P2ase, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PI3-K, phosphatidylinositol 3-kinase; SREBP-1c, sterol regulatory element binding protein 1c; STZ, streptozotocin; WT, wild-type.
Received September 26, 2003.
Accepted for publication November 3, 2003.
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