Overexpression of the P46 (T1) Translocase Component of the Glucose-6-phosphatase Complex in Hepatocytes Impairs Glycogen Accumulation via Hydrolysis of Glucose 1-Phosphate

The final step of gluconeogenesis and glycogenolysis is catalyzed by the glucose-6-phosphatase (Glc-6-Pase) enzyme complex, located in the endoplasmic reticulum. The complex consists of a 36-kDa catalytic subunit (P36), a 46-kDa glucose 6-phosphate translocase (P46), and putative glucose and inorganic phosphate transporters. Mutations in the genes encoding P36 or P46 have been linked to glycogen storage diseases type Ia and type Ib, respectively. However, the relative roles of these two proteins in control of the rate of glucose 6-phosphate hydrolysis have not been defined. To gain insight into this area, we have constructed a recombinant adenovirus containing the cDNA encoding human P46 (AdCMV-P46) and treated rat hepatocytes with this virus, or a virus encoding P36 (AdCMV-P36), or the combination of both viruses, resulting in large and equivalent increases in expression of the transgenes within 8–24 h of viral treatment. The overexpressed P46 protein was appropriately targeted to hepatocyte microsomes and caused a 58% increase in glucose 6-phosphate hydrolysis in nondetergent-treated (intact) microsomal preparations relative to controls, whereas overexpression of P36 caused a 3.6-fold increase. Overexpression of P46 caused a 50% inhibition of glycogen accumulation in hepatocytes from fasted rats incubated at 25 mm glucose relative to cells treated with a control virus (AdCMV-βGAL). Furthermore, in hepatocytes from fed rats cultured at 25 mm glucose and then exposed to 15 mm glucose, AdCMV-P46 treatment activated glycogenolysis, as indicated by a 50% reduction in glycogen content relative to AdCMV-βGAL-treated controls. In contrast, overexpression of P46 had only small effects on glycolysis, whereas overexpression of P36 had large effects on both glycogen metabolism and glycolysis, even in the presence of co-overexpressed glucokinase. Finally, P46 overexpression enhanced glucose 1-phosphate but not fructose 6-phosphate hydrolysis in intact microsomes, providing a mechanism by which P46 overexpression may exert its preferential effects on glycogen metabolism. The final step of gluconeogenesis and glycogenolysis is catalyzed by the glucose-6-phosphatase (Glc-6-Pase) enzyme complex, located in the endoplasmic reticulum. The complex consists of a 36-kDa catalytic subunit (P36), a 46-kDa glucose 6-phosphate translocase (P46), and putative glucose and inorganic phosphate transporters. Mutations in the genes encoding P36 or P46 have been linked to glycogen storage diseases type Ia and type Ib, respectively. However, the relative roles of these two proteins in control of the rate of glucose 6-phosphate hydrolysis have not been defined. To gain insight into this area, we have constructed a recombinant adenovirus containing the cDNA encoding human P46 (AdCMV-P46) and treated rat hepatocytes with this virus, or a virus encoding P36 (AdCMV-P36), or the combination of both viruses, resulting in large and equivalent increases in expression of the transgenes within 8–24 h of viral treatment. The overexpressed P46 protein was appropriately targeted to hepatocyte microsomes and caused a 58% increase in glucose 6-phosphate hydrolysis in nondetergent-treated (intact) microsomal preparations relative to controls, whereas overexpression of P36 caused a 3.6-fold increase. Overexpression of P46 caused a 50% inhibition of glycogen accumulation in hepatocytes from fasted rats incubated at 25 mm glucose relative to cells treated with a control virus (AdCMV-βGAL). Furthermore, in hepatocytes from fed rats cultured at 25 mm glucose and then exposed to 15 mm glucose, AdCMV-P46 treatment activated glycogenolysis, as indicated by a 50% reduction in glycogen content relative to AdCMV-βGAL-treated controls. In contrast, overexpression of P46 had only small effects on glycolysis, whereas overexpression of P36 had large effects on both glycogen metabolism and glycolysis, even in the presence of co-overexpressed glucokinase. Finally, P46 overexpression enhanced glucose 1-phosphate but not fructose 6-phosphate hydrolysis in intact microsomes, providing a mechanism by which P46 overexpression may exert its preferential effects on glycogen metabolism. catalytic subunit of glucose-6-phosphatase putative glucose 6-phosphate translocase endoplasmic reticulum kilobase pairs The glucose-6-phosphatase enzyme complex catalyzes the final step of gluconeogenesis. The complex is composed of a catalytic subunit of 36 kDa (P36)1sequestered within the endoplasmic reticulum (ER), a 46-kDa glucose-6-phosphate translocase known as P46 or T1 that delivers glucose 6-phosphate to the catalytic subunit, and putative ER glucose and inorganic phosphate (Pi) transporters (T2 and T3) that move the reaction products back into the cytosol (1Nordlie R.C. Curr. Top. Cell. Regul. 1974; 8: 33-117Crossref PubMed Scopus (119) Google Scholar, 2Arion W.J. Lange A.J. Walls E.H. Ballas I.M. J. Biol. Chem. 1980; 255: 10396-10406Abstract Full Text PDF PubMed Google Scholar, 3van de Werve G. Lange A. Newgard C. Mechin M.-C. Li Y. Berteloot A. Eur. J. Biochem. 2000; 267: 1533-1549Crossref PubMed Scopus (118) Google Scholar). However, only P36 and P46 have been clearly identified and cloned (4Shelly L.L. Lei K.J. Pan C.-J. Sakata S.F. Ruppert S. Schutz G. Chou J.Y. J. Biol. Chem. 1993; 268: 21482-21485Abstract Full Text PDF PubMed Google Scholar, 5Lei K.J. Shelly L.L. Pan C.J. Sidbury J.B. Chou J.Y. Science. 1993; 262: 580-583Crossref PubMed Scopus (314) Google Scholar, 6Lange A.J. Argaud D. El-Maghrabi M.R. Pan W. Maitra S.R. Pilkis S.J. Biochem. Biophys. Res. Commun. 1994; 201: 302-309Crossref PubMed Scopus (116) Google Scholar, 7Gerin I. Veiga-da-Cunha M. Achouri Y. Collet J.-F. Van Schaftingen E. FEBS Lett. 1997; 419: 235-238Crossref PubMed Scopus (191) Google Scholar). It remains uncertain whether Pi transport is embodied in the function of P46 or encoded by a separate protein (8Van Schaftingen E. Veiga-da-Cunha M. Gerin I. Moukil M. Matschinsky F.M. Magnuson M.A. Molecular Pathogenesis of MODYs. 15. Karger, Basel2000: 136-152Google Scholar). Furthermore, glucose A. Biochem. J. PubMed Scopus (118) Google been A. Biochem. J. PubMed Scopus Google in P36 and P46 have both been linked to glycogen storage diseases in human K.J. Shelly L.L. Pan C.J. Sidbury J.B. Chou J.Y. Science. 1993; 262: 580-583Crossref PubMed Scopus (314) Google Scholar, M. Gerin I. de de C. I. A. S. M. Van Schaftingen E. J. Full Text Full Text PDF PubMed Scopus Google Scholar). with type Ia glycogen storage have in the P36 K.J. Shelly L.L. Pan C.J. Sidbury J.B. Chou J.Y. Science. 1993; 262: 580-583Crossref PubMed Scopus (314) Google and a of glucose-6-phosphatase of whether the is in intact or microsomal preparations Y. Google Scholar). with type glycogen storage have in the P46 M. Gerin I. de de C. I. A. S. M. Van Schaftingen E. J. Full Text Full Text PDF PubMed Scopus Google and have or glucose-6-phosphatase in intact microsomes but or in preparations A.J. W.J. J. Biol. Chem. 1980; 255: Full Text PDF PubMed Google the human clearly that both the P36 and P46 products glucose 6-phosphate the relative by these proteins to the and to of of insight into this is to of the glucose-6-phosphatase recombinant adenovirus to P36 in cells C. Lange A. Newgard J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google hepatocytes J. Lange A.J. Newgard J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google or of rats Lange A.J. Newgard J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of P36 caused increases in glucose 6-phosphate hydrolysis in both cultured C. Lange A. Newgard J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Lange A.J. Newgard J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google and in intact in glucose and a 50% in glycogen Lange A.J. Newgard J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, the of overexpression of P36 in the was the in glucose by the that of the complex as P46 to the rate at which is of the was to the of P46 in the glucose-6-phosphatase complex by overexpression of the protein in rat that overexpression of P46 increases hydrolysis in intact microsomes, not to the as overexpression of the catalytic Overexpression of P46 inhibition of glycogen and of glycogenolysis, but only small effects on glycolysis, whereas overexpression of P36 effects on both The preferential of P46 overexpression on glycogen metabolism may to its to the hydrolysis of a phosphate of glycogen glucose cDNA encoding the T1 of the glucose-6-phosphatase complex was cloned on the of its to the products and which phosphate phosphate and phosphate I. Veiga-da-Cunha M. Achouri Y. Collet J.-F. Van Schaftingen E. FEBS Lett. 1997; 419: 235-238Crossref PubMed Scopus (191) Google Scholar, Schaftingen E. Veiga-da-Cunha M. Gerin I. Moukil M. Matschinsky F.M. Magnuson M.A. Molecular Pathogenesis of MODYs. 15. Karger, Basel2000: 136-152Google Scholar). The to the putative P46 was to at in and with a in the glucose-6-phosphatase The that the cloned was a of the glucose-6-phosphatase enzyme complex was the of in the in two human with type glycogen storage M. Gerin I. de de C. I. A. S. M. Van Schaftingen E. J. Full Text Full Text PDF PubMed Scopus Google Scholar). However, the function of P46 in cells not been the of the was to insight into the and of this protein its overexpression in rat glycogen storage is by of glucose-6-phosphatase in intact microsomes but or in preparations Y. Google Scholar). The of type glycogen storage to the the glucose-6-phosphatase complex, in which the of P46 is to as glucose the catalytic subunit to gain to its W.J. Lange A.J. Walls E.H. Ballas I.M. J. Biol. Chem. 1980; 255: 10396-10406Abstract Full Text PDF PubMed Google Scholar). The in its that the translocase function was the on of glucose 6-phosphate hydrolysis in with intact However, that in the of glucose 6-phosphate hydrolysis in intact and microsomes, whereas at the rate in the intact preparations but in the A. de Werve G. J. Biol. Chem. Full Text PDF PubMed Google Scholar). was to a of the translocase and of the glucose-6-phosphatase complex, with of a in or both proteins de Werve G. Lange A. Newgard C. Mechin M.-C. Li Y. Berteloot A. Eur. J. Biochem. 2000; 267: 1533-1549Crossref PubMed Scopus (118) Google Scholar, A. de Werve G. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The of the two proteins is by in which of the catalytic subunit of glucose 6-phosphate transport into microsomes Pan C.-J. Chou PubMed Scopus Google the that overexpression of P46 is to the of the glucose-6-phosphatase enzyme this the The P46 is targeted to a of the overexpressed protein to the endoplasmic reticulum in intact Overexpression of P46 glucose and glucose 1-phosphate hydrolysis in intact microsomes, on in However, the that the of P46 overexpression on hydrolysis in intact microsomes is the of overexpression of that of the control is in the of the not clearly or of the of glucose-6-phosphatase complex the hydrolysis with P46 overexpression by the transport or a Overexpression of P46 clearly glycogen accumulation in hepatocytes from fasted rats and of glycogenolysis in hepatocytes from fed P46 overexpression effects on or in to the effects of overexpressed P46 is overexpressed P36 at the of and glycogen by a in the of by the intact glucose-6-phosphatase we have that both and by intact microsomes from control at to the rate of of these at a of overexpression of P46 increases but not that the may a the glucose-6-phosphatase a mechanism by which P46 overexpression glycogen metabolism relative to its effects on in hepatocytes from fasted P46 overexpression increases glycogenolysis in is a phosphate that is to glycogen metabolism. hydrolysis of of glycogen the of the is the of glycogen In hepatocytes with P46 overexpression to a in glucose of the of the glycogen reaction in of glycogen and the of the glucose-6-phosphatase complex to to the effects of overexpressed P46 on glycogen we have the that P46 the glucose-6-phosphatase complex with proteins or that glycogen metabolism. is that glucose in and glycogen metabolism in within in the fasted enzyme is to of the enzyme in the its to protein Schaftingen E. M. M. J. 1994; 8: PubMed Scopus Google Scholar, M. Biochem. J. 1993; PubMed Scopus Google Scholar, 1997; PubMed Scopus Google Scholar). In the glucose the of from the to the The of glycogen metabolism in glycogen is from to the in to glucose and resulting in of glycogen in a from the the of the de Werve G. Lange A. Newgard C. Mechin M.-C. Li Y. Berteloot A. Eur. J. Biochem. 2000; 267: 1533-1549Crossref PubMed Scopus (118) Google Scholar, A. D. S. Eur. J. Biochem. PubMed Scopus Google Scholar, D. S. Biochem. J. 1997; PubMed Scopus Google Scholar). of glycogen within cells is by of protein to the glycogen is by glycogen of protein which to to the of glycogen as a glycogen in 2000; PubMed Scopus Google Scholar). The of this glycogen Biochem. PubMed Scopus Google with the of the glucose-6-phosphatase complex, the that these two to whether and the of the P46 T1 translocase in this may have to of of glucose metabolism and the control of glucose glycogen in of human I. J. PubMed Scopus Google Scholar, I. J. 1994; PubMed Google Scholar, G. G. J. PubMed Scopus Google but the this not is enhanced the glucose-6-phosphatase with this been that with type have a to glucose by glucose the to that of glucose-6-phosphatase is M. A. Y. M. J. PubMed Scopus Google Scholar). To of the of glucose-6-phosphatase in on the expression of the P36 catalytic subunit, to the that P36 expression is in to and in and cultured cells Newgard J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. W. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. M. D. 1997; PubMed Google Scholar). was that P46 expression was in M.-C. de Werve G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google by de Werve G. Biochem. Biophys. Res. Commun. 2000; PubMed Scopus Google Scholar). the of in expression and of the P46 subunit with to its on glycogen storage in type The glucose-6-phosphatase enzyme complex catalyzes the final step of gluconeogenesis. The complex is composed of a catalytic subunit of 36 kDa (P36)1sequestered within the endoplasmic reticulum (ER), a 46-kDa glucose-6-phosphate translocase known as P46 or T1 that delivers glucose 6-phosphate to the catalytic subunit, and putative ER glucose and inorganic phosphate (Pi) transporters (T2 and T3) that move the reaction products back into the cytosol (1Nordlie R.C. Curr. Top. Cell. Regul. 1974; 8: 33-117Crossref PubMed Scopus (119) Google Scholar, 2Arion W.J. Lange A.J. Walls E.H. Ballas I.M. J. Biol. Chem. 1980; 255: 10396-10406Abstract Full Text PDF PubMed Google Scholar, 3van de Werve G. Lange A. Newgard C. Mechin M.-C. Li Y. Berteloot A. Eur. J. Biochem. 2000; 267: 1533-1549Crossref PubMed Scopus (118) Google Scholar). However, only P36 and P46 have been clearly identified and cloned (4Shelly L.L. Lei K.J. Pan C.-J. Sakata S.F. Ruppert S. Schutz G. Chou J.Y. J. Biol. Chem. 1993; 268: 21482-21485Abstract Full Text PDF PubMed Google Scholar, 5Lei K.J. Shelly L.L. Pan C.J. Sidbury J.B. Chou J.Y. Science. 1993; 262: 580-583Crossref PubMed Scopus (314) Google Scholar, 6Lange A.J. Argaud D. El-Maghrabi M.R. Pan W. Maitra S.R. Pilkis S.J. Biochem. Biophys. Res. Commun. 1994; 201: 302-309Crossref PubMed Scopus (116) Google Scholar, 7Gerin I. Veiga-da-Cunha M. Achouri Y. Collet J.-F. Van Schaftingen E. FEBS Lett. 1997; 419: 235-238Crossref PubMed Scopus (191) Google Scholar). It remains uncertain whether Pi transport is embodied in the function of P46 or encoded by a separate protein (8Van Schaftingen E. Veiga-da-Cunha M. Gerin I. Moukil M. Matschinsky F.M. Magnuson M.A. Molecular Pathogenesis of MODYs. 15. Karger, Basel2000: 136-152Google Scholar). Furthermore, glucose A. Biochem. J. PubMed Scopus (118) Google been A. Biochem. J. PubMed Scopus Google Scholar). Mutations in P36 and P46 have both been linked to glycogen storage diseases in human K.J. Shelly L.L. Pan C.J. Sidbury J.B. Chou J.Y. Science. 1993; 262: 580-583Crossref PubMed Scopus (314) Google Scholar, M. Gerin I. de de C. I. A. S. M. Van Schaftingen E. J. Full Text Full Text PDF PubMed Scopus Google Scholar). with type Ia glycogen storage have in the P36 K.J. Shelly L.L. Pan C.J. Sidbury J.B. Chou J.Y. Science. 1993; 262: 580-583Crossref PubMed Scopus (314) Google and a of glucose-6-phosphatase of whether the is in intact or microsomal preparations Y. Google Scholar). with type glycogen storage have in the P46 M. Gerin I. de de C. I. A. S. M. Van Schaftingen E. J. Full Text Full Text PDF PubMed Scopus Google and have or glucose-6-phosphatase in intact microsomes but or in preparations A.J. W.J. J. Biol. Chem. 1980; 255: Full Text PDF PubMed Google Scholar). the human clearly that both the P36 and P46 products glucose 6-phosphate the relative by these proteins to the and to of of insight into this is to of the glucose-6-phosphatase recombinant adenovirus to P36 in cells C. Lange A. Newgard J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google hepatocytes J. Lange A.J. Newgard J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google or of rats Lange A.J. Newgard J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of P36 caused increases in glucose 6-phosphate hydrolysis in both cultured C. Lange A. Newgard J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Lange A.J. Newgard J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google and in intact in glucose and a 50% in glycogen Lange A.J. Newgard J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, the of overexpression of P36 in the was the in glucose by the that of the complex as P46 to the rate at which is The of the was to the of P46 in the glucose-6-phosphatase complex by overexpression of the protein in rat that overexpression of P46 increases hydrolysis in intact microsomes, not to the as overexpression of the catalytic Overexpression of P46 inhibition of glycogen and of glycogenolysis, but only small effects on glycolysis, whereas overexpression of P36 effects on both The preferential of P46 overexpression on glycogen metabolism may to its to the hydrolysis of a phosphate of glycogen glucose cDNA encoding the T1 of the glucose-6-phosphatase complex was cloned on the of its to the products and which phosphate phosphate and phosphate I. Veiga-da-Cunha M. Achouri Y. Collet J.-F. Van Schaftingen E. FEBS Lett. 1997; 419: 235-238Crossref PubMed Scopus (191) Google Scholar, Schaftingen E. Veiga-da-Cunha M. Gerin I. Moukil M. Matschinsky F.M. Magnuson M.A. Molecular Pathogenesis of MODYs. 15. Karger, Basel2000: 136-152Google Scholar). The to the putative P46 was to at in and with a in the glucose-6-phosphatase The that the cloned was a of the glucose-6-phosphatase enzyme complex was the of in the in two human with type glycogen storage M. Gerin I. de de C. I. A. S. M. Van Schaftingen E. J. Full Text Full Text PDF PubMed Scopus Google Scholar). However, the function of P46 in cells not been the of the was to insight into the and of this protein its overexpression in rat glycogen storage is by of glucose-6-phosphatase in intact microsomes but or in preparations Y. Google Scholar). The of type glycogen storage to the the glucose-6-phosphatase complex, in which the of P46 is to as glucose the catalytic subunit to gain to its W.J. Lange A.J. Walls E.H. Ballas I.M. J. Biol. Chem. 1980; 255: 10396-10406Abstract Full Text PDF PubMed Google Scholar). The in its that the translocase function was the on of glucose 6-phosphate hydrolysis in with intact However, that in the of glucose 6-phosphate hydrolysis in intact and microsomes, whereas at the rate in the intact preparations but in the A. de Werve G. J. Biol. Chem. Full Text PDF PubMed Google Scholar). was to a of the translocase and of the glucose-6-phosphatase complex, with of a in or both proteins de Werve G. Lange A. Newgard C. Mechin M.-C. Li Y. Berteloot A. Eur. J. Biochem. 2000; 267: 1533-1549Crossref PubMed Scopus (118) Google Scholar, A. de Werve G. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The of the two proteins is by in which of the catalytic subunit of glucose 6-phosphate transport into microsomes Pan C.-J. Chou PubMed Scopus Google the that overexpression of P46 is to the of the glucose-6-phosphatase enzyme this the The P46 is targeted to a of the overexpressed protein to the endoplasmic reticulum in intact Overexpression of P46 glucose and glucose 1-phosphate hydrolysis in intact microsomes, on in However, the that the of P46 overexpression on hydrolysis in intact microsomes is the of overexpression of that of the control is in the of the not clearly or of the of glucose-6-phosphatase complex the hydrolysis with P46 overexpression by the transport or a Overexpression of P46 clearly glycogen accumulation in hepatocytes from fasted rats and of glycogenolysis in hepatocytes from fed P46 overexpression effects on or in to the effects of overexpressed P46 is overexpressed P36 at the of and glycogen by a in the of by the intact glucose-6-phosphatase we have that both and by intact microsomes from control at to the rate of of these at a of overexpression of P46 increases but not that the may a the glucose-6-phosphatase a mechanism by which P46 overexpression glycogen metabolism relative to its effects on in hepatocytes from fasted P46 overexpression increases glycogenolysis in is a phosphate that is to glycogen metabolism. hydrolysis of of glycogen the of the is the of glycogen In hepatocytes with P46 overexpression to a in glucose of the of the glycogen reaction in of glycogen and the of the glucose-6-phosphatase complex to to the effects of overexpressed P46 on glycogen we have the that P46 the glucose-6-phosphatase complex with proteins or that glycogen metabolism. is that glucose in and glycogen metabolism in within in the fasted enzyme is to of the enzyme in the its to protein Schaftingen E. M. M. J. 1994; 8: PubMed Scopus Google Scholar, M. Biochem. J. 1993; PubMed Scopus Google Scholar, 1997; PubMed Scopus Google Scholar). In the glucose the of from the to the The of glycogen metabolism in glycogen is from to the in to glucose and resulting in of glycogen in a from the the of the de Werve G. Lange A. Newgard C. Mechin M.-C. Li Y. Berteloot A. Eur. J. Biochem. 2000; 267: 1533-1549Crossref PubMed Scopus (118) Google Scholar, A. D. S. Eur. J. Biochem. PubMed Scopus Google Scholar, D. S. Biochem. J. 1997; PubMed Scopus Google Scholar). of glycogen within cells is by of protein to the glycogen is by glycogen of protein which to to the of glycogen as a glycogen in 2000; PubMed Scopus Google Scholar). The of this glycogen Biochem. PubMed Scopus Google with the of the glucose-6-phosphatase complex, the that these two to whether and the of the P46 T1 translocase in this may have to of of glucose metabolism and the control of glucose glycogen in of human I. J. PubMed Scopus Google Scholar, I. J. 1994; PubMed Google Scholar, G. G. J. PubMed Scopus Google but the this not is enhanced the glucose-6-phosphatase with this been that with type have a to glucose by glucose the to that of glucose-6-phosphatase is M. A. Y. M. J. PubMed Scopus Google Scholar). To of the of glucose-6-phosphatase in on the expression of the P36 catalytic subunit, to the that P36 expression is in to and in and cultured cells Newgard J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. W. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. M. D. 1997; PubMed Google Scholar). was that P46 expression was in M.-C. de Werve G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google by de Werve G. Biochem. Biophys. Res. Commun. 2000; PubMed Scopus Google Scholar). the of in expression and of the P46 subunit with to its on glycogen storage in type The cDNA encoding the T1 of the glucose-6-phosphatase complex was cloned on the of its to the products and which phosphate phosphate and phosphate I. Veiga-da-Cunha M. Achouri Y. Collet J.-F. Van Schaftingen E. FEBS Lett. 1997; 419: 235-238Crossref PubMed Scopus (191) Google Scholar, Schaftingen E. Veiga-da-Cunha M. Gerin I. Moukil M. Matschinsky F.M. Magnuson M.A. Molecular Pathogenesis of MODYs. 15. Karger, Basel2000: 136-152Google Scholar). The to the putative P46 was to at in and with a in the glucose-6-phosphatase The that the cloned was a of the glucose-6-phosphatase enzyme complex was the of in the in two human with type glycogen storage M. Gerin I. de de C. I. A. S. M. Van Schaftingen E. J. Full Text Full Text PDF PubMed Scopus Google Scholar). However, the function of P46 in cells not been the of the was to insight into the and of this protein its overexpression in rat glycogen storage is by of glucose-6-phosphatase in intact microsomes but or in preparations Y. Google Scholar). The of type glycogen storage to the the glucose-6-phosphatase complex, in which the of P46 is to as glucose the catalytic subunit to gain to its W.J. Lange A.J. Walls E.H. Ballas I.M. J. Biol. Chem. 1980; 255: 10396-10406Abstract Full Text PDF PubMed Google Scholar). The in its that the translocase function was the on of glucose 6-phosphate hydrolysis in with intact However, that in the of glucose 6-phosphate hydrolysis in intact and microsomes, whereas at the rate in the intact preparations but in the A. de Werve G. J. Biol. Chem. Full Text PDF PubMed Google Scholar). was to a of the translocase and of the glucose-6-phosphatase complex, with of a in or both proteins de Werve G. Lange A. Newgard C. Mechin M.-C. Li Y. Berteloot A. Eur. J. Biochem. 2000; 267: 1533-1549Crossref PubMed Scopus (118) Google Scholar, A. de Werve G. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The of the two proteins is by in which of the catalytic subunit of glucose 6-phosphate transport into microsomes Pan C.-J. Chou PubMed Scopus Google Scholar). The the that overexpression of P46 is to the of the glucose-6-phosphatase enzyme this the The P46 is targeted to a of the overexpressed protein to the endoplasmic reticulum in intact Overexpression of P46 glucose and glucose 1-phosphate hydrolysis in intact microsomes, on in However, the that the of P46 overexpression on hydrolysis in intact microsomes is the of overexpression of that of the control is in the of the not clearly or of the of glucose-6-phosphatase complex the hydrolysis with P46 overexpression by the transport or a Overexpression of P46 clearly glycogen accumulation in hepatocytes from fasted rats and of glycogenolysis in hepatocytes from fed P46 overexpression effects on or in to the effects of overexpressed P46 is overexpressed P36 at the of and glycogen by a in the of by the intact glucose-6-phosphatase we have that both and by intact microsomes from control at to the rate of of these at a of overexpression of P46 increases but not that the may a the glucose-6-phosphatase a mechanism by which P46 overexpression glycogen metabolism relative to its effects on in hepatocytes from fasted P46 overexpression increases glycogenolysis in is a phosphate that is to glycogen metabolism. hydrolysis of of glycogen the of the is the of glycogen In hepatocytes with P46 overexpression to a in glucose of the of the glycogen reaction in of glycogen and the of the glucose-6-phosphatase complex to to the effects of overexpressed P46 on glycogen we have the that P46 the glucose-6-phosphatase complex with proteins or that glycogen metabolism. is that glucose in and glycogen metabolism in within in the fasted enzyme is to of the enzyme in the its to protein Schaftingen E. M. M. J. 1994; 8: PubMed Scopus Google Scholar, M. Biochem. J. 1993; PubMed Scopus Google Scholar, 1997; PubMed Scopus Google Scholar). In the glucose the of from the to the The of glycogen metabolism in glycogen is from to the in to glucose and resulting in of glycogen in a from the the of the de Werve G. Lange A. Newgard C. Mechin M.-C. Li Y. Berteloot A. Eur. J. Biochem. 2000; 267: 1533-1549Crossref PubMed Scopus (118) Google Scholar, A. D. S. Eur. J. Biochem. PubMed Scopus Google Scholar, D. S. Biochem. J. 1997; PubMed Scopus Google Scholar). of glycogen within cells is by of protein to the glycogen is by glycogen of protein which to to the of glycogen as a glycogen in 2000; PubMed Scopus Google Scholar). The of this glycogen Biochem. PubMed Scopus Google with the of the glucose-6-phosphatase complex, the that these two to whether and the of the P46 T1 translocase in this The may have to of of glucose metabolism and the control of glucose glycogen in of human I. J. PubMed Scopus Google Scholar, I. J. 1994; PubMed Google Scholar, G. G. J. PubMed Scopus Google but the this not is enhanced the glucose-6-phosphatase with this been that with type have a to glucose by glucose the to that of glucose-6-phosphatase is M. A. Y. M. J. PubMed Scopus Google Scholar). To of the of glucose-6-phosphatase in on the expression of the P36 catalytic subunit, to the that P36 expression is in to and in and cultured cells Newgard J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. W. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. M. D. 1997; PubMed Google Scholar). was that P46 expression was in M.-C. de Werve G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google by de Werve G. Biochem. Biophys. Res. Commun. 2000; PubMed Scopus Google Scholar). the of in expression and of the P46 subunit with to its on glycogen storage in type Van Schaftingen of the P46 cDNA and of the and and and

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