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• W2022890619 abstract "Overexpression of the glucose-phosphorylating enzyme glucokinase (GK) or members of the family of glycogen-targeting subunits of protein phosphatase-1 increases hepatic glucose disposal and glycogen synthesis. This study was undertaken to evaluate the functional properties of a novel, truncated glycogen-targeting subunit derived from the skeletal muscle isoform GM/RGl and to compare pathways of glycogen metabolism and their regulation in cells with overexpressed targeting subunits and GK. When overexpressed in hepatocytes, truncated GM/RGl (GMΔC) was approximately twice as potent as full-length GM/RGl in stimulation of glycogen synthesis, but clearly less potent than GK or two other native glycogen-targeting subunits, GL and PTG. We also found that cells with overexpressed GMΔC are unique in that glycogen was efficiently degraded in response to lowering of media glucose concentrations, stimulation with forskolin, or a combination of both maneuvers, whereas cells with overexpressed GL, PTG, or GK exhibited impairment in one or both of these glycogenolytic signaling pathways. 2H NMR analysis of purified glycogen revealed that hepatocytes with overexpressed GK synthesized a larger portion of their glycogen from triose phosphates and a smaller portion from tricarboxylic acid cycle intermediates than cells with overexpressed glycogen-targeting subunits. Additional evidence for activation of distinct pathways of glycogen synthesis by GK and targeting subunits is provided by the additive effect of co-overexpression of the two types of proteins upon glycogen synthesis and a much larger stimulation of glucose utilization, glucose transport, and lactate production elicited by GK. We conclude that overexpression of the novel targeting subunit GMΔC confers unique regulation of glycogen metabolism. Furthermore, targeting subunits and GK stimulate glycogen synthesis by distinct pathways. Overexpression of the glucose-phosphorylating enzyme glucokinase (GK) or members of the family of glycogen-targeting subunits of protein phosphatase-1 increases hepatic glucose disposal and glycogen synthesis. This study was undertaken to evaluate the functional properties of a novel, truncated glycogen-targeting subunit derived from the skeletal muscle isoform GM/RGl and to compare pathways of glycogen metabolism and their regulation in cells with overexpressed targeting subunits and GK. When overexpressed in hepatocytes, truncated GM/RGl (GMΔC) was approximately twice as potent as full-length GM/RGl in stimulation of glycogen synthesis, but clearly less potent than GK or two other native glycogen-targeting subunits, GL and PTG. We also found that cells with overexpressed GMΔC are unique in that glycogen was efficiently degraded in response to lowering of media glucose concentrations, stimulation with forskolin, or a combination of both maneuvers, whereas cells with overexpressed GL, PTG, or GK exhibited impairment in one or both of these glycogenolytic signaling pathways. 2H NMR analysis of purified glycogen revealed that hepatocytes with overexpressed GK synthesized a larger portion of their glycogen from triose phosphates and a smaller portion from tricarboxylic acid cycle intermediates than cells with overexpressed glycogen-targeting subunits. Additional evidence for activation of distinct pathways of glycogen synthesis by GK and targeting subunits is provided by the additive effect of co-overexpression of the two types of proteins upon glycogen synthesis and a much larger stimulation of glucose utilization, glucose transport, and lactate production elicited by GK. We conclude that overexpression of the novel targeting subunit GMΔC confers unique regulation of glycogen metabolism. Furthermore, targeting subunits and GK stimulate glycogen synthesis by distinct pathways. glucokinase plaque-forming units Hepatic glucose production is poorly controlled in type II diabetes due to increased gluconeogenesis and impaired glycogen storage (1Magnusson I. Rothman D.L. Katz L.D. Shulman R.G. Shulman G.I. J. Clin. Invest. 1992; 90: 1323-1327Google Scholar, 2Cline G.W. Rothman D.L. Magnusson I. Katz L.D. Shulman G.I. J. Clin. Invest. 1994; 94: 2369-2376Google Scholar, 3Velho G. Petersen K.F. Perseghin G. Hwang J.H. Rothman D.L. Pueyo M.E. Cline G.W. Froguel P. Shulman G.I. J. Clin. Invest. 1996; 98: 1755-1761Google Scholar). The glucose-phosphorylating enzyme glucokinase (GK)1 plays a key role in determining the balance between glucose disposal and production in the liver. Increased expression of GK in hepatoma cells (4Valera A. Bosch F. Eur. J. Biochem. 1994; 222: 533-539Google Scholar), isolated hepatocytes (5O'Doherty R.M. Lehman D.L. Seoane J. Gomez-Foix A.M. Guinovart J.J. Newgard C.B. J. Biol. Chem. 1996; 271: 20524-20530Google Scholar, 6Seoane J. Gomez-Foix A.M. O'Doherty R.M. Gomez-Ara C. Newgard C.B. Guinovart J.J. J. Biol. Chem. 1996; 271: 23756-23760Google Scholar), and livers of intact animals (7Ferre T. Pujol A. Efren R. Bosch F. Valera A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7225-7230Google Scholar, 8O'Doherty R.M. Lehman D. Telemaque-Potts S. Newgard C.B. Diabetes. 1999; 48: 2022-2027Google Scholar, 9Hariharan N. Farrelly D. Hagan D. Hillyer D. Arbeeny C. Sabrah T. Treloar A. Brown K. Kalinowski S. Mookhtiar K. Diabetes. 1997; 46: 11-16Google Scholar, 10Niswender K.D. Shiota M. Postic C. Cherrington A.D. Magnuson M.A. J. Biol. Chem. 1997; 272: 22570-22575Google Scholar) potently affects glucose disposal and glycogen deposition. Conversely, overexpression of key components of the glucose-6-phosphatase enzyme complex, which catalyzes glucose 6-phosphate hydrolysis, causes a sharp reduction in glycogen storage in liver cells (11Seoane J. Trinh K. O'Doherty R. Gomez-Foix A.M. Lange A.J. Newgard C.B. Guinovart J.J. J. Biol. Chem. 1997; 272: 26972-26977Google Scholar, 12Trinh K. O'Doherty R. Anderson P. Lange A.J. Newgard C.B. J. Biol. Chem. 1998; 273: 31615-31620Google Scholar, 13An J. Li Y. van de Werve G. Newgard C.B. J. Biol. Chem. 2001; 276: 10722-10729Google Scholar).Although the control strength of GK in hepatic glucose metabolism is substantial, it has become clear that it is also possible to stimulate glycogen synthesis by expression of proteins that function distal to the glucose phosphorylation step. In particular, recent studies have highlighted an important role for glycogen-targeting subunits of protein phosphatase-1 in spatial organization and regulation of glycogen metabolism (14Newgard C.B. Brady M.J. O'Doherty R.M. Saltiel A.R. Diabetes. 2000; 49: 1967-1977Google Scholar). Four members of a gene family encoding these proteins are known. GM or RGl (hereafter referred to as GM/RGl) is expressed primarily in striated skeletal muscle (15Tang P.M. Bondor J.A. Swiderek K.M. DePaoli-Roach A.A. J. Biol. Chem. 1991; 266: 15782-15789Google Scholar); GL is expressed primarily in liver (16Doherty M.J. Moorhead G. Morrice N. Cohen P. Cohen P.T. FEBS Lett. 1995; 375: 294-298Google Scholar); and PTG (protein targeting toglycogen) (17Printen J.A. Brady M.J. Saltiel A.R. Science. 1997; 275: 1475-1478Google Scholar, 18Doherty M.J. Young P.R. Cohen P.T. FEBS Lett. 1996; 399: 339-343Google Scholar) and PPPR6 (19Armstrong C.G. Browne G.J. Cohen P. Cohen P.T. FEBS Lett. 1997; 418: 210-214Google Scholar) are expressed in a wide range of tissues. These proteins bind to glycogen and protein phosphatase-1 and have differential capacities for binding to glycogen synthase, glycogen phosphorylase, and phosphorylase kinase (14Newgard C.B. Brady M.J. O'Doherty R.M. Saltiel A.R. Diabetes. 2000; 49: 1967-1977Google Scholar, 15Tang P.M. Bondor J.A. Swiderek K.M. DePaoli-Roach A.A. J. Biol. Chem. 1991; 266: 15782-15789Google Scholar, 16Doherty M.J. Moorhead G. Morrice N. Cohen P. Cohen P.T. FEBS Lett. 1995; 375: 294-298Google Scholar, 17Printen J.A. Brady M.J. Saltiel A.R. Science. 1997; 275: 1475-1478Google Scholar, 18Doherty M.J. Young P.R. Cohen P.T. FEBS Lett. 1996; 399: 339-343Google Scholar, 19Armstrong C.G. Browne G.J. Cohen P. Cohen P.T. FEBS Lett. 1997; 418: 210-214Google Scholar). Overexpression of these proteins in mammalian cells results in stimulation of glycogen synthesis (17Printen J.A. Brady M.J. Saltiel A.R. Science. 1997; 275: 1475-1478Google Scholar, 20Berman H.K. O'Doherty R.M. Anderson P. Newgard C.B. J. Biol. Chem. 1998; 273: 26421-26425Google Scholar), but with differential potency and response to regulatory factors, as recently demonstrated in a study comparing the effects of overexpressed PTG, GL, and GM/RGl in isolated hepatocytes (21Gasa R. Jensen P.B. Berman H.K. Brady M.J. DePaoli-Roach A.A. Newgard C.B. J. Biol. Chem. 2000; 275: 26396-26403Google Scholar). Overexpressed GL was the most effective targeting subunit for stimulation of glycogen synthesis, consistent with its superior capacity to activate glycogen synthase, and cells with overexpressed PTG were least responsive to forskolin as a glycogenolytic stimulus. Interestingly, cells with overexpressed GM/RGlexhibited a modest increase in glycogen storage, but also responded to forskolin by lowering glycogen to levels similar to those of control cells. The relatively weak glycogenic effect of overexpressed GM/RGl may be related to structural differences between this targeting subunit and other family members, most notably its long C-terminal tail containing a putative sarcoplasmic reticulum-binding domain that is absent in other isoforms. The brisk response to forskolin in GM/RGl-overexpressing cells may occur via protein kinase A-mediated phosphorylation of a serine in its protein phosphatase-1-binding site; this protein kinase A consensus site is lacking in targeting subunits other than GM/RGl (14Newgard C.B. Brady M.J. O'Doherty R.M. Saltiel A.R. Diabetes. 2000; 49: 1967-1977Google Scholar).Increased expression of GK in livers of normal rats results in lowering of blood glucose levels and increased glycogen deposition, but these are accompanied by a large increase in circulating triglycerides and fatty acids (8O'Doherty R.M. Lehman D. Telemaque-Potts S. Newgard C.B. Diabetes. 1999; 48: 2022-2027Google Scholar). PTG overexpression in livers of normal rats also improves glucose tolerance, but in contrast to GK, does so without perturbing lipid homeostasis (22O'Doherty R.M. Jensen P.B. Anderson P. Jones J.G. Berman H.K. Kearney D. Newgard C.B. J. Clin. Invest. 2000; 105: 479-488Google Scholar). However, animals with increased hepatic PTG expression exhibit very high liver glycogen levels after an overnight fast (22O'Doherty R.M. Jensen P.B. Anderson P. Jones J.G. Berman H.K. Kearney D. Newgard C.B. J. Clin. Invest. 2000; 105: 479-488Google Scholar), consistent with the poor response of PTG-overexpressing hepatocytes to forskolin and glucagon (20Berman H.K. O'Doherty R.M. Anderson P. Newgard C.B. J. Biol. Chem. 1998; 273: 26421-26425Google Scholar, 21Gasa R. Jensen P.B. Berman H.K. Brady M.J. DePaoli-Roach A.A. Newgard C.B. J. Biol. Chem. 2000; 275: 26396-26403Google Scholar). Furthermore, oral delivery of [13C]glucose to PTG-overexpressing animals and analysis of glycogen/glucose by NMR revealed that the majority of glycogen is synthesized by an indirect pathway (e.g. a pathway other than glucose → glucose-6-P → glucose-1-P → UDP-glucose → glycogen).This study was designed to address two fundamental questions raised by the foregoing work. First, is it possible to design a glycogen-targeting subunit of protein phosphatase-1 that has a potent stimulatory effect on glucose disposal and glycogen deposition while still allowing normal regulation of glycogenolysis in response to catabolic signals? Second, are there differences in the metabolic fate of glucose in cells with overexpressed glycogen-targeting subunits relative to cells with overexpressed GK? In answer to these questions, we show that a truncated form of GM/RGl lacking its long C-terminal tail has a significantly enhanced glycogenic effect compared with native GM/RGl, but with retention of effective glycogenolytic signaling. We have also evaluated pathways of glycogen synthesis in living cells via administration of2H2O and application of NMR (23Jones J.G. Solomon M.A. Cole S.M. Sherry A.D. Malloy C.R. Am. J. Physiol. 2001; 281: E848-E856Google Scholar) to identify the 2H-labeled carbon atoms in the glucose molecules of purified glycogen. This analysis revealed that overexpression of glycogen-targeting subunits or GK in hepatocytes activates discrete and complementary pathways of glucose disposal.DISCUSSIONHepatic glycogen stores are depleted in all major forms of diabetes (1Magnusson I. Rothman D.L. Katz L.D. Shulman R.G. Shulman G.I. J. Clin. Invest. 1992; 90: 1323-1327Google Scholar, 2Cline G.W. Rothman D.L. Magnusson I. Katz L.D. Shulman G.I. J. Clin. Invest. 1994; 94: 2369-2376Google Scholar, 3Velho G. Petersen K.F. Perseghin G. Hwang J.H. Rothman D.L. Pueyo M.E. Cline G.W. Froguel P. Shulman G.I. J. Clin. Invest. 1996; 98: 1755-1761Google Scholar). For example, activity-lowering mutations in the glucokinase gene cause maturity-onset diabetes of youth type II, and patients experience a clear decline in liver glycogen stores (3Velho G. Petersen K.F. Perseghin G. Hwang J.H. Rothman D.L. Pueyo M.E. Cline G.W. Froguel P. Shulman G.I. J. Clin. Invest. 1996; 98: 1755-1761Google Scholar). Animals with experimental suppression of GK expression in liver exhibit a similar deficit (33Postic C. Shiota M. Niswender K.D. Jetton T.L. Chen Y.J. Moates J.M. Shelton K.D. Lindner J. Cherrington A.D. Magnuson M.A. J. Biol. Chem. 1999; 274: 305-315Google Scholar). The potential role of glycogen-targeting subunits of protein phosphatase-1 in the pathogenesis of diabetes is less clear (see Ref. 14Newgard C.B. Brady M.J. O'Doherty R.M. Saltiel A.R. Diabetes. 2000; 49: 1967-1977Google Scholar for review), in part because genetic analysis of all of the different members of the gene family has not yet been accomplished. However, overexpression of one family member, PTG, stimulates glycogen synthesis and improves glucose disposal without perturbation of lipid homeostasis in rodents (22O'Doherty R.M. Jensen P.B. Anderson P. Jones J.G. Berman H.K. Kearney D. Newgard C.B. J. Clin. Invest. 2000; 105: 479-488Google Scholar). Thus, this study continues a line of investigation in our laboratory in which GK and glycogen-targeting subunits are being evaluated as potential therapeutic targets for enhancing hepatic glucose disposal and lowering blood glucose levels in diabetes (14Newgard C.B. Brady M.J. O'Doherty R.M. Saltiel A.R. Diabetes. 2000; 49: 1967-1977Google Scholar, 20Berman H.K. O'Doherty R.M. Anderson P. Newgard C.B. J. Biol. Chem. 1998; 273: 26421-26425Google Scholar, 21Gasa R. Jensen P.B. Berman H.K. Brady M.J. DePaoli-Roach A.A. Newgard C.B. J. Biol. Chem. 2000; 275: 26396-26403Google Scholar, 22O'Doherty R.M. Jensen P.B. Anderson P. Jones J.G. Berman H.K. Kearney D. Newgard C.B. J. Clin. Invest. 2000; 105: 479-488Google Scholar).This study had two major goals. The first was to compare the metabolic and regulatory properties of hepatocytes overexpressing a truncated form of GM/RGl (GMΔC) with those of cells with overexpressed GK or native glycogen-targeting subunit isoforms. The second was to investigate the distinct pathways by which GK and glycogen-targeting subunits stimulate glycogen synthesis in liver cells. The accomplishment of these goals has led to the following key findings. 1) Cells with overexpressed GMΔC accumulate more glycogen than cells with overexpression of wild-type GM/RGl, but not as much as cells with overexpressed PTG, GL, or GK. 2) The molecules tested can be divided into three classes with regard to responses to glycogenolytic signals. Cells with overexpressed PTG or GLare poorly responsive to lowering of media glucose concentrations or addition of forskolin. GK-overexpressing cells exhibit an intermediate response, with brisk glycogenolysis in response to lowering of media glucose concentrations, but with a poor response to forskolin and no additive response to a combination of low glucose and forskolin. Finally, cells with overexpressed GMΔC are unique in that they activate glycogenolysis in response to lowering of media glucose concentrations, stimulation with forskolin, or a combination of both maneuvers. Thus, overexpression of GMΔC causes significant stimulation of glycogen deposition, but with retention of exquisite sensitivity to nutritional and pharmacological catabolic signals. 3) The difference in sensitivity to glycogenolytic agents of cells with overexpressed GMΔC relative to cells with overexpressed PTG is not reflective of stimulation of different pathways of glycogen synthesis. Thus, analysis of2H2O labeling of glycogen/glucose shows essentially identical patterns for cells with overexpressed GMΔC or PTG at either glucose concentration tested, with major contributions made by the direct pathway and flux from the level of the trichloroacetic acid cycle and a smaller contribution from the triose phosphates. 4) The labeling pattern just described for cells with overexpressed targeting subunits is clearly different from that for cells with overexpressed GK, with a larger contribution of flux from the triose phosphates apparent in GK-overexpressing cells at either glucose concentration. Additional evidence for activation of distinct and complementary pathways of glycogen synthesis by GK and targeting subunit overexpression is provided by the additive effect of the two types of proteins on glycogen synthesis and the much more dramatic stimulation of glucose utilization, glucose uptake, and lactate production caused by overexpression of GK.The mechanism underlying the enhanced glycogenic potency of GMΔC versus native GM/RGl is unknown. Possible explanations include the following. 1) Removal of the C-terminal domain alters the nature of interactions of GM/RGl with protein phosphatase-1 and/or with the protein phosphatase-1 substrates, glycogen synthase, phosphorylase kinase, and glycogen phosphorylase. 2) Removal of the C-terminal domain prevents interaction of GM/RGl with cellular membranes, allowing more of the protein to bind to glycogen. 3) A combination of these possibilities may be the explanation. Consistent with possibility 2, the C-terminal region of GM/RGl contains a patch of hydrophobic amino acids that may mediate binding of the native protein to membranes of the sarcoplasmic reticulum in muscle (34Hubbard M.J. Dent P. Smythe C. Cohen P. FEBS Lett. 1990; 189: 245-249Google Scholar). Glycogen particles accumulate around the sarcoplasmic reticulum in muscle, suggesting that targeting of key enzymes to this site may be facilitated/guided by GM/RGl. When the native GM/RGl protein is overexpressed in hepatocytes, which lack sarcoplasmic reticulum, this may cause “mistargeting” of GM/RGl to membranes or other cellular sites that are non-ideal environments for glycogen synthesis. In this model, removal of the C terminus of GM/RGl may allow the molecule to target mainly to glycogen, enhancing its stimulatory effect on deposition of the glucose polymer.Another interesting feature of cells with overexpressed GMΔC is their enhanced capacity for response to catabolic stimuli relative to cells with overexpression of other targeting subunits or GK. Native GM/RGl differs from other targeting subunits in that it has two serine-containing consensus sequences for protein kinase A-mediated phosphorylation. Indeed, phosphorylation of one of these serines, residing within the known protein phosphatase-1-binding site (serine 67 in the human GM/RGl sequence), has been reported to be stimulated by glycogenolytic agents such as forskolin, resulting in disassociation of protein phosphatase-1 (35Dent P. Lavoinne A. Nakielny S. Watt P. Cohen P. Nature. 1990; 348: 302-308Google Scholar, 36Wu J. Kleiner U. Brautigan D.L. Biochemistry. 1996; 35: 13858-13864Google Scholar). Of note is the fact that truncated GMΔC and native GM/RGl share the consensus protein kinase A sites, and their overexpression in hepatocytes results in the same brisk responses to forskolin (Fig. 2). Whether phosphorylation of these sites is sufficient to explain the responses to both the nutritional and pharmacological glycogenolytic signals remains to be tested.This work clearly demonstrates that glycogen-targeting subunits and GK stimulate glycogen accumulation by distinct mechanisms. In the2H2O labeling experiments, the fundamental difference in the glycogen labeling pattern between these groups of cells was the relatively large contribution of carbon from the level of triose phosphates (indicated by labeling of carbon 3 of glucose) in GK-overexpressing cells, which was replaced by a larger portion of labeling from the level of trichloroacetic acid cycle intermediates (indicated by labeling of carbon 6) in cells with overexpressed targeting subunits. Based on these findings and the data of Figs. 6 and7 that demonstrate increased glucose consumption, glucose uptake, and lactate output in GK-overexpressing cells, we propose the following model to explain our results (see Fig.10 for schematic summary). In cells with overexpressed glycogen-targeting subunits, activation of glycogen synthase exerts a pull on the glucose 6-phosphate pool, which in turn activates gluconeogenesis from 2- and 3-carbon precursors and uptake of glucose. Since the medium contained little or no glycerol, fructose, or other immediate precursors of the triose phosphates, the main precursors used for glycogen synthesis under these conditions are likely to be those that pass through the mitochondrial compartment and the fumarase reaction on their way to glucose 6-phosphate,e.g. pyruvate, lactate, and amino acids, all of which are abundant in the culture medium. In cells with overexpressed GK, the glucose 6-phosphate pool is expanded by the increase in glucose phosphorylation (6Seoane J. Gomez-Foix A.M. O'Doherty R.M. Gomez-Ara C. Newgard C.B. Guinovart J.J. J. Biol. Chem. 1996; 271: 23756-23760Google Scholar). A large portion of this glucose 6-phosphate is pushed directly into glycogen, facilitated in part by the known allosteric activation of glycogen synthase by this metabolic intermediate. However, an even larger percentage of the pool enters glycolysis, making the major contribution to the fall in media glucose concentration and the rise in lactate. A portion of this flux apparently represents metabolism of glucose 6-phosphate to the level of the triose phosphates, where labeling at carbon 3 occurs, followed by incorporation of these labeled precursors into glycogen. With the major contributions of the direct (hexose phosphates → glycogen) and modified direct (hexose phosphates → triose phosphates → hexose phosphates→ glycogen) pathways to glycogen synthesis in GK-overexpressing cells, gluconeogenesis from the level of trichloroacetic acid cycle intermediates is not stimulated.What, then, are the implications of our findings for whole animal physiology and diabetes therapy? First, our work establishes that most of the glucose 6-phosphate produced by GK overexpression enters glycolysis, with a far smaller portion contributing to glycogen synthesis. Thus, although GK overexpression will clearly lower circulating glucose concentrations, there will also be undesirable increases in lactate production and lipogenesis, consistent with our previous findings (8O'Doherty R.M. Lehman D. Telemaque-Potts S. Newgard C.B. Diabetes. 1999; 48: 2022-2027Google Scholar). In previous studies, adenovirus-mediated overexpression of PTG in normal rats resulted in improved disposal of an oral glucose load relative to controls, with no perturbation of lipid homeostasis (22O'Doherty R.M. Jensen P.B. Anderson P. Jones J.G. Berman H.K. Kearney D. Newgard C.B. J. Clin. Invest. 2000; 105: 479-488Google Scholar). However, these animals did not lower their liver glycogen levels in response to fasting, in effect presenting with a phenotype of glycogen storage disease. In this study, we have described a novel, modified glycogen-targeting subunit (GMΔC) that appears to provide substantial stimulation of glycogen accumulation while also allowing the cells to remain sensitive to two different kinds of catabolic signals. It will be of interest to test this targeting isoform in the in vivo setting. Hepatic glucose production is poorly controlled in type II diabetes due to increased gluconeogenesis and impaired glycogen storage (1Magnusson I. Rothman D.L. Katz L.D. Shulman R.G. Shulman G.I. J. Clin. Invest. 1992; 90: 1323-1327Google Scholar, 2Cline G.W. Rothman D.L. Magnusson I. Katz L.D. Shulman G.I. J. Clin. Invest. 1994; 94: 2369-2376Google Scholar, 3Velho G. Petersen K.F. Perseghin G. Hwang J.H. Rothman D.L. Pueyo M.E. Cline G.W. Froguel P. Shulman G.I. J. Clin. Invest. 1996; 98: 1755-1761Google Scholar). The glucose-phosphorylating enzyme glucokinase (GK)1 plays a key role in determining the balance between glucose disposal and production in the liver. Increased expression of GK in hepatoma cells (4Valera A. Bosch F. Eur. J. Biochem. 1994; 222: 533-539Google Scholar), isolated hepatocytes (5O'Doherty R.M. Lehman D.L. Seoane J. Gomez-Foix A.M. Guinovart J.J. Newgard C.B. J. Biol. Chem. 1996; 271: 20524-20530Google Scholar, 6Seoane J. Gomez-Foix A.M. O'Doherty R.M. Gomez-Ara C. Newgard C.B. Guinovart J.J. J. Biol. Chem. 1996; 271: 23756-23760Google Scholar), and livers of intact animals (7Ferre T. Pujol A. Efren R. Bosch F. Valera A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7225-7230Google Scholar, 8O'Doherty R.M. Lehman D. Telemaque-Potts S. Newgard C.B. Diabetes. 1999; 48: 2022-2027Google Scholar, 9Hariharan N. Farrelly D. Hagan D. Hillyer D. Arbeeny C. Sabrah T. Treloar A. Brown K. Kalinowski S. Mookhtiar K. Diabetes. 1997; 46: 11-16Google Scholar, 10Niswender K.D. Shiota M. Postic C. Cherrington A.D. Magnuson M.A. J. Biol. Chem. 1997; 272: 22570-22575Google Scholar) potently affects glucose disposal and glycogen deposition. Conversely, overexpression of key components of the glucose-6-phosphatase enzyme complex, which catalyzes glucose 6-phosphate hydrolysis, causes a sharp reduction in glycogen storage in liver cells (11Seoane J. Trinh K. O'Doherty R. Gomez-Foix A.M. Lange A.J. Newgard C.B. Guinovart J.J. J. Biol. Chem. 1997; 272: 26972-26977Google Scholar, 12Trinh K. O'Doherty R. Anderson P. Lange A.J. Newgard C.B. J. Biol. Chem. 1998; 273: 31615-31620Google Scholar, 13An J. Li Y. van de Werve G. Newgard C.B. J. Biol. Chem. 2001; 276: 10722-10729Google Scholar). Although the control strength of GK in hepatic glucose metabolism is substantial, it has become clear that it is also possible to stimulate glycogen synthesis by expression of proteins that function distal to the glucose phosphorylation step. In particular, recent studies have highlighted an important role for glycogen-targeting subunits of protein phosphatase-1 in spatial organization and regulation of glycogen metabolism (14Newgard C.B. Brady M.J. O'Doherty R.M. Saltiel A.R. Diabetes. 2000; 49: 1967-1977Google Scholar). Four members of a gene family encoding these proteins are known. GM or RGl (hereafter referred to as GM/RGl) is expressed primarily in striated skeletal muscle (15Tang P.M. Bondor J.A. Swiderek K.M. DePaoli-Roach A.A. J. Biol. Chem. 1991; 266: 15782-15789Google Scholar); GL is expressed primarily in liver (16Doherty M.J. Moorhead G. Morrice N. Cohen P. Cohen P.T. FEBS Lett. 1995; 375: 294-298Google Scholar); and PTG (protein targeting toglycogen) (17Printen J.A. Brady M.J. Saltiel A.R. Science. 1997; 275: 1475-1478Google Scholar, 18Doherty M.J. Young P.R. Cohen P.T. FEBS Lett. 1996; 399: 339-343Google Scholar) and PPPR6 (19Armstrong C.G. Browne G.J. Cohen P. Cohen P.T. FEBS Lett. 1997; 418: 210-214Google Scholar) are expressed in a wide range of tissues. These proteins bind to glycogen and protein phosphatase-1 and have differential capacities for binding to glycogen synthase, glycogen phosphorylase, and phosphorylase kinase (14Newgard C.B. Brady M.J. O'Doherty R.M. Saltiel A.R. Diabetes. 2000; 49: 1967-1977Google Scholar, 15Tang P.M. Bondor J.A. Swiderek K.M. DePaoli-Roach A.A. J. Biol. Chem. 1991; 266: 15782-15789Google Scholar, 16Doherty M.J. Moorhead G. Morrice N. Cohen P. Cohen P.T. FEBS Lett. 1995; 375: 294-298Google Scholar, 17Printen J.A. Brady M.J. Saltiel A.R. Science. 1997; 275: 1475-1478Google Scholar, 18Doherty M.J. Young P.R. Cohen P.T. FEBS Lett. 1996; 399: 339-343Google Scholar, 19Armstrong C.G. Browne G.J. Cohen P. Cohen P.T. FEBS Lett. 1997; 418: 210-214Google Scholar). Overexpression of these proteins in mammalian cells results in stimulation of glycogen synthesis (17Printen J.A. Brady M.J. Saltiel A.R. Science. 1997; 275: 1475-1478Google Scholar, 20Berman H.K. O'Doherty R.M. Anderson P. Newgard C.B. J. Biol. Chem. 1998; 273: 26421-26425Google Scholar), but with differential potency and response to regulatory factors, as recently demonstrated in a study comparing the effects of overexpressed PTG, GL, and GM/RGl in isolated hepatocytes (21Gasa R. Jensen P.B. Berman H.K. Brady M.J. DePaoli-Roach A.A. Newgard C.B. J. Biol. Chem. 2000; 275: 26396-26403Google Scholar). Overexpressed GL was the most effective targeting subunit for stimulation of glycogen synthesis, consistent with its superior capacity to activate glycogen synthase, and cells with overexpressed PTG were least responsive to forskolin as a glycogenolytic stimulus. Interestingly, cells with overexpressed GM/RGlexhibited a modest increase in glycogen storage, but also responded to forskolin by lowering glycogen to levels similar to those of control cells. The relatively weak glycogenic effect of overexpressed GM/RGl may be related to structural differences between this targeting subunit and other family members, most notably its long C-terminal tail containing a putative sarcoplasmic reticulum-binding domain that is absent in other isoforms. The brisk response to" @default.
• W2022890619 created "2016-06-24" @default.
• W2022890619 creator A5039095005 @default.
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• W2022890619 date "2002-01-01" @default.
• W2022890619 modified "2023-09-27" @default.
• W2022890619 title "Glycogen-targeting Subunits and Glucokinase Differentially Affect Pathways of Glycogen Metabolism and Their Regulation in Hepatocytes" @default.
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