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RECEPTORS AND SIGNAL TRANSDUCTION
1Department of Medicine and 2Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio
Submitted 1 July 2005 ; accepted in final form 14 September 2005
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ABSTRACT |
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5-aminoimidazole-4-carboxamide-1-
-D-ribofuranoside; extracellular signal related-kinase 1/2; phospho-extracellular signal related-kinase 1/2; N-acetyl-L-cysteine; diamide; acetyl-CoA carboxylase; phospho-acetyl-CoA carboxylase
The mechanism underlying the activation of Glut1 is under active study (1, 2, 25), and several potential mechanisms have been proposed to explain the stimulation of Glut1-mediated glucose transport. These mechanisms include homooligomerization of Glut1, an increase in the intrinsic catalytic turnover of the transporter, dissociation or association of regulating proteins, posttranslational modification of the transporter, and translocation of the transporter from intracellular sites to the plasma membrane (2, 11, 13). However, strong evidence for any of the above (and other) proposals is currently lacking.
In addition, the sequence of mediating events, signal, and effectors that link the inhibition of oxidative phosphorylation to the stimulation of glucose transport has remained unresolved. Profound changes that occur after inhibition of oxidative phosphorylation by cyanide or azide include 1) a rapid fall in cell ATP level that returns to normal within an hour despite the continuous presence of the inhibitors (18, 30), with ATP synthesis occurring by a marked stimulation of glucose transport and glycolysis (13, 17, 18); 2) an important change that occurs universally and sustains the enhanced rate of glycolysis, the changed redox state, with an increase in cytosolic NADH-to-NAD+ ratio (3, 16, 32); and 3) stimulation of 5'-AMP-activated protein kinase (AMPK), which results from the associated changes in cell AMP-to-ATP ratio (1, 10). However, whether any of the above changes is necessary and sufficient for the observed stimulation of glucose transport remains unknown.
In the present study, we examined whether an increase in cell NADH-to-NAD+ ratio brought about by conditions other than inhibition of oxidative phosphorylation can also lead to stimulation of glucose transport; we used lactate and ethanol to increase the NADH-to-NAD+ ratio. We also tested whether increase in reactive oxygen species (ROS), presumably resulting from the action of NADH oxidase or from mitochondria in the case of azide, is a potential mediator of the glucose transport response. Finally, we explored the possibility that stimulation of AMPK plays an important role in the enhancement of glucose transport, and we present data in favor of this latter hypothesis.
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MATERIALS AND METHODS |
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-D-ribofuranoside (AICAR), and standard chemicals were from Sigma (St. Louis, MO). Rabbit anti-AMPK-
-pan, rabbit monoclonal anti-phospho-AMPK- (Thr172), rabbit anti-phospho-acetyl-CoA carboxylase (ACC) (Ser79), and rabbit anti-ACC were from Upstate Cell Signaling Solutions (Charlottesville, VA). Mouse monoclonal anti-phospho-ERK1/2 antibody and rabbit anti-total ERK antibody were from Santa Cruz Biotechnology (Santa Cruz, CA).
Cell culture.
Clone 9 cells were maintained in DMEM containing 5.6 mM D-glucose supplemented with 10% calf serum at 37°C in a 9% CO2 humidified chamber (pH 7.4). Cells were used between passages 30 and 50. On confluence (at 3–4 days), the medium was replaced with serum-free DMEM for 24 h. Cells were treated with diluent (small volume of DMEM), 5 mM azide, 15 mM lactate (pH 7.4), 1% (167 mM) ethanol, 10 mM -mercaptoethanol (-ME), or other agents for 1 h before glucose transport assay or cell lysis for Western blotting or immunoprecipitation. In certain experiments, 16.7 mM ethanol (final concentration) was used.
Measurement of [3H]3-OMG uptake. Confluent cells in triplicate 60-mm dishes were incubated for 60 s in glucose uptake medium containing either DMSO alone or DMSO containing CB at a final concentration of 50 µM. The uptake medium consisted of 1.0 ml DMEM containing 1.0 µCi of [3H]3-OMG and 1 µl of CB solution or DMSO. Uptake was stopped by an ice-cold solution of 100 mM MgCl2 and 10 µM phloretin (18). Cells were harvested in 1 ml of H2O, and radioactivity was determined by scintillation spectrometry. [3H]3-OMG uptake was calculated as the difference in uptake in the absence and presence of CB, assayed in parallel. Each experiment was repeated three or more times, and the results were averaged. Uptake measurements in control and treated cells were performed in parallel.
Measurement of ATP, ADP, and AMP by HPLC. Confluent cells on 100-mm dishes were used in these assays. Twenty-four hours before the treatment, cells were washed twice with PBS before being changed to fresh serum-free DMEM. After 1 h of exposure to diluent, azide, lactate, or ethanol, the medium was removed, and 0.5 ml of ice-cold 0.25 M perchloric acid was added to dishes that were kept on ice for an additional 5 min. Harvested materials were centrifuged at 14,000 g for 10 min. The supernatant was neutralized with 110 µl of 1 M KOH, and tubes were kept on ice for an additional 30 min. The resulting precipitate was removed by centrifugation, and the supernatant was stored at –80°C until it was analyzed. The perchloric acid pellet was dissolved in 50 µl of 1 M NaOH and diluted up to 500 µl with H2O for assay of protein.
Two hundred fifty microliters of neutralized cell extract were used for separation of ATP, ADP, and AMP, which was carried out by gradient HPLC with a reverse-phase column. A 3-µm Supelcosil LC-18-T reverse-phase analytical column (15 cm x 4.6-mm inner diameter; Supelco, Bellefonte, PA) was used. Mobile phases used for the gradient system were buffer A (0.1 M KH2PO4, pH 6.0) and buffer B, consisting of buffer A plus 15% methanol (vol/vol). All buffers and solutions used for HPLC analysis were filtered and degassed through a 0.45-µm filter (Rainin Instrument, Woburn, MA). Identification and quantitative measurements of nucleotides were carried out by the injection of standard solutions of nucleotides with known concentrations. Standard curves were plotted for individual compounds and were used to determine the content of ATP, ADP, and AMP in each sample.
Assay of NAD+ and NADH. Confluent cells in 15-cm dishes were treated with different reagents as described above. Pooled cells from two dishes were used for each assay. Extraction in acidic solution was performed for analysis of NAD+ (5, 28). Cells were scraped off the dishes in 1.5 ml of PBS, 100 µl of the cell suspension was taken for protein assay, and the rest of the cells were collected by centrifugation and resuspended in 80 µl of 1 M HClO4 containing 20 µl of Hanks' buffer used as pH indicator. Samples were centrifuged, and supernatants were neutralized with 20 µl of 4 M KOH. A 50-µl aliquot was used as blank, and another 50 µl was used in the alcohol dehydrogenase (ADH) reaction.
Extraction in alkali solution was performed for analysis of NADH (5, 28). Cells were harvested as above, resuspended in 150 µl of 0.5 M KOH in 70% ethanol, and heated to 90°C for 5 min. Suspensions were cooled and neutralized with 60 µl of triethanolamine mixture (0.5 M triethanolamine, 0.4 M KH2PO4, and 0.1 M K2HPO4). Samples were centrifuged for 10 min at 14,000 g, and 100 µl was used for the blank and another 100 µl for the L-lactic dehydrogenase (LDH) reaction.
NAD+ and NADH were assayed with spectrophotometric enzymatic assays (5, 28). To measure NAD+, samples were incubated with ADH to convert NAD+ to NADH, and the change in absorbance was measured at 340 nm. NADH was measured by using LDH to convert NADH to NAD+, and the decrease in absorbance at 340 nm before and after the reaction was taken as a measure of the amount. A standard curve of NADH was used for calculation.
SDS-PAGE and Western blotting.
Cell lysates were prepared with a buffer containing (in mM) 75 NaCl, 25 Tris (pH 7.5), 25 sodium fluoride, 5 sodium pyrophosphate, 1 sodium orthovanadate, and 0.1 PMSF with 0.5 mg/l leupeptin, 1 mg/l aprotinin, and 0.5% Nonidet P-40 (NP-40). Lysates were centrifuged at 14,000 g for 20 min to remove nuclei and insoluble materials. A sample was taken for protein assay. In certain experiments, whole cell lysates were prepared by scraping the cells directly into SDS lysis buffer (5% SDS, 0.5 M Tris at pH 6.8, 1.0% -ME, 10% glycerol, and 0.02% bromphenol blue). Samples were boiled for 5 min and vortexed until they were no longer viscous. Protein samples were separated by 10% SDS-PAGE and transferred to polyvinylidene difluoride (PVDF) membranes. The membrane was blocked with 5% nonfat milk and then incubated with mouse anti-phospho-ERK1/2, rabbit anti-total ERK, rabbit anti-phospho-AMPK, rabbit anti-phospho-ACC, rabbit anti-total ACC, or rabbit anti-AMPK--pan in Tris-buffered saline-Tween 20 [TBST; 50 mM Tris, 150 mM NaCl, and 0.05% Tween 20 (vol/vol)]. The secondary antibody was a 1:500–1:2,000 dilution of horseradish peroxidase-conjugated goat anti-rabbit antibody or goat-anti-mouse antibody diluted in TBST. Blots were developed with ECL reagents, immunoreactive bands were visualized on Kodak X-Omat film, and the intensity of the bands was determined by densitometry. Each experiment was repeated at least three times, and the results were averaged.
Immunoprecipitation of phospho-AMPK.
Two hundred micrograms of protein from postnuclear cell lysates with NP-40 buffer was immunoprecipitated overnight at 4°C with prewashed protein G Sepharose and 2 µl of rabbit anti-phospho-AMPK directed against 1- and 2-isoforms of the enzyme phosphorylated at Thr172. Samples were centrifuged at 3,000 rpm for 1 min at 4°C, and the pellets were washed three times with 10 vols of ice-cold 0.5% NP-40 buffer. The final pellet was lysed in SDS buffer and loaded in 10% SDS-PAGE. Gels were transferred to PVDF membranes and probed with 1:1,000 rabbit anti-AMPK--pan (directed against both -subunits) and goat anti-rabbit secondary antibody.
Statistical analysis. ANOVA was used to assess significance throughout. In experiments measuring cell adenine nucleotide content, Student's t-test was used because all treatments were not performed in parallel. P < 0.05 was considered significant.
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RESULTS |
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5- to 12-fold) to 1.7, 0.74, and 0.89 in azide-, lactate-, and ethanol-treated cells, respectively.
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The increase in cytosolic reduced state may also be associated with a parallel change in redox state of glutathione with an increase in reduced form of glutathione (GSH) and an increase in cell GSH-to-GSSG ratio. In keeping with this possibility, exposure of cells to 10 mM -ME for 2 h resulted in a 1.7 ± 0.1-fold stimulation of glucose transport, an effect that was completely blocked by coincubation in the presence of 0.3 mM diamide (an intracellular sulfhydryl oxidizing agent). We then tested whether exposure to diamide inhibits the stimulatory effect of azide on glucose transport (Fig. 5). As can be appreciated, exposure to diamide alone had no effect on glucose transport, and, importantly, the stimulatory of azide on glucose transport was not altered by coincubation with diamide.
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Effect of azide, lactate, and ethanol on cell ATP, ADP, and AMP levels and on ADP-to-ATP and AMP-to-ATP ratios. Because the increased generation of ROS did not appear to mediate the transport response to the agents, we examined their effect on levels of adenosine nucleotides. In previous studies (18, 30), we found that cell ATP levels decrease markedly soon after inhibition of oxidative phosphorylation following exposure to azide or cyanide and recover to normal levels within an hour despite the continued presence of the inhibitors. We therefore examined the possibility that cellular energy state is likewise altered after exposure to lactate and ethanol. ATP, ADP, and AMP levels in cells treated with diluent, azide, lactate, and ethanol for 15 min are summarized in Table 1. ATP level was reduced in cells treated with azide, whereas AMP levels were increased after 15 min of exposure to all three agents. After 60 min of exposure, the levels returned to normal except for the AMP level in azide-treated cells, which remained more than twofold higher than in control cells (data not shown).
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1- and 2-subunits of the enzyme in Western blots of extracts of cells treated with the above agents (Fig. 7A). Alternatively, Western blots of total AMPK were prepared from samples immunoprecipitated by anti-phospho-AMPK antibody (Fig. 7B). Increased phosphorylation of AMPK was evident in cells treated with AICAR, azide, lactate, and ethanol, both in cell lysates and phospho-AMPK immunoprecipitates.
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DISCUSSION |
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In the present study, we made the novel observation that an imposed increase in cell NADH-to-NAD+ ratio brought about by exposure of cells to ethanol or lactate results in stimulation of glucose transport. The observed increase in the ratio of NADH to NAD+ was predicted based on the known metabolism of ethanol to acetaldehyde and acetate and increase in lactate-to-pyruvate ratio on addition of lactate, both conditions that increase the NADH-to-NAD+ ratio. The rise in cell NADH, in turn, was associated with an increase in ROS production that was reflected by increased phosphorylation of ERK1/2 (33). We also found that an imposed presumed increase in cell GSH-to-GSSG ratio was associated with an increase in the rate of glucose transport. However, and surprisingly, the stimulation of transport following inhibition of oxidative phosphorylation by azide was not inhibited by the addition of NAC, an intracellular reducing agent that counteracts ROS, or diamide, an intracellular sulfydryl oxidizing agent (3, 33). The results indicate that whereas exposure to azide, ethanol, or lactate increases cell NADH-to-NAD+ ratio and stimulates ROS generation, the stimulation of glucose transport does not appear to be mediated by increased ROS generation.
We then made the novel observation that, similar to exposure to azide, incubation in presence of ethanol and lactate also leads to a transient decrease in cell ATP and an increase in ADP and AMP levels resulting in a significant increase at 15 min in cell ADP-to-ATP and AMP-to-ATP ratios, which return to near-normal levels at 60 min. The transient decrease in ATP levels is in keeping with our previous observations and reflects the decrease in ATP production following inhibition of oxidative phosphorylation and the subsequent recovery of ATP level to normal levels through enhancements of glucose transport and ATP generation through glycolysis (13, 17, 18). However, the mechanism by which exposure to ethanol and lactate results in a rise in ADP-to-ATP and AMP-to-ATP ratios is less clear. It is known that the metabolism of both ethanol and lactate requires use of NAD+, resulting in its conversion to NADH. It is hence possible that the relative depletion in NAD+ limits the rate of glycolysis by limiting the conversion of glyceraldehyde-3-phosphate to 1,3-diphosphoglycerate at the glyceraldehyde-3-phosphate dehydrogenase step. Further studies are required to directly examine this possibility.
In a previous study, it was reported that exposure of human lymphocytes or cell lines expressing Glut1 to ethanol (up to 200 mM) results in an inhibition of glucose transport and that the effect is not observed in transfected cells expressing Glut3 or Glut4 (14). The effect was measurable with either 3-OMG or 2-deoxyglucose, suggesting that the observed inhibitory effect of ethanol is not on phosphorylation of transported glucose. Although the reasons for the discrepancy between this report and our results are not clear, it is possible that the short period of exposure (a few minutes) to ethanol in the above study may not have allowed the stimulation of transport observed in our study (which utilized a 1-h exposure period) to become apparent. Because glucose transport may be stimulated in cells exposed to hyperosmolarity (2, 12), we performed several experiments with 17 mM ethanol (instead of 167 mM). We noted that the stimulatory effect of ethanol on the rate of glucose transport was evident at the lower (17 mM) concentration.
The observed alterations in cell ATP, ADP, and AMP levels resulting in a rise in AMP-to-ATP ratios in cells exposed to azide, ethanol, and lactate would be expected to stimulate AMPK (10). In previous studies we (1) and others (2) reported that exposure of Clone 9 cells expressing the Glut1 isoform to AICAR, an agent that stimulates AMPK phosphorylation and activity, is associated with an augmentation of the rate of glucose transport. Although most studies on the effect of AMPK on glucose transport have been performed in cells that express both Glut4 and Glut1 (10), it is clear that glucose transport is also stimulated in cells expressing only the Glut1 isoform (1, 2). A stimulation of glucose transport and AMPK was recently reported in adult rat cardiomyocytes exposed to dinitrophenol, an uncoupler of mitochondrial oxidative phosphorylation (22). Those authors found that the stimulation of glucose transport was partially blocked by inhibition of AMPK activity. In contrast, a report in Clone 9 cells showed that the stimulation of glucose transport following activation of AMPK is completely blocked by inhibition of p38 MAPK (34), a signaling molecule thought to be downstream to AMPK (22, 34). In the present study we found that exposure of cells to the three agents under study (azide, lactate, or ethanol) stimulates AMPK measured by its phosphorylation and reflected by an increased phosphorylation of ACC (21). Although the exact mechanism by which increased AMPK activity leads to stimulation of glucose transport is not known at present, the increase in AMP-to-ATP ratio following inhibition of oxidative phosphorylation in conjunction with the stimulation of glucose transport in response to AICAR makes it likely that activation of AMPK mediates the glucose transport in response to azide, ethanol, and lactate (1, 2). This possibility is further strengthened by our novel observation that exposure of cells to ethanol and lactate stimulates both AMPK activity and glucose transport. In the absence of direct evidence implicating the role of AMPK in the glucose transport response, and without knowledge of the sequential steps between stimulation of AMPK and enhancement of glucose transport, the linkage between the two remains speculative. Hence, further studies are necessary to directly establish the mediating role of stimulation of AMPK activity and the subsequent downstream events in the glucose transport response.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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