TY - JOUR
T1 - Identification of a mammalian glycerol-3-phosphate phosphatase
T2 - Role in metabolism and signaling in pancreatic β-cells and hepatocytes
AU - Mugabo, Yves
AU - Zhao, Shangang
AU - Seifried, Annegrit
AU - Gezzar, Sari
AU - Al-Mass, Anfal
AU - Zhang, Dongwei
AU - Lamontagne, Julien
AU - Attane, Camille
AU - Poursharifi, Pegah
AU - Iglesias, José
AU - Joly, Erik
AU - Peyot, Marie Line
AU - Gohla, Antje
AU - Madiraju, S. R.Murthy
AU - Prentki, Marc
N1 - Funding Information:
The authors thank the Metabolomics Core Facility of the Centre de Recherche du Centre Hospitalier de l''Université de Montreál for performing the metabolite determinations. This study was supported by grants from Canadian Institutes of Health Research (to M.P. and S.R.M.M.), NIH Grant R01-DK19514 (to M.P. and Neil Ruderman, Boston University), Deutsche Forschungsgemeinschaft Grant SFB688 (to A.G.), Forschungszentrum Grant FZ82 (to A.G.), and a fellowship from Fond de Recherche Santé Québec (to Y.M.). M.P. holds the Canada Research Chair in Diabetes and Metabolism.
PY - 2016/1/26
Y1 - 2016/1/26
N2 - Obesity, and the associated disturbed glycerolipid/fatty acid (GL/FA) cycle, contribute to insulin resistance, islet β-cell failure, and type 2 diabetes. Flux through the GL/FA cycle is regulated by the availability of glycerol-3-phosphate (Gro3P) and fatty acyl-CoA. We describe here amammalian Gro3P phosphatase (G3PP), which was not known to exist in mammalian cells, that can directly hydrolyze Gro3P to glycerol. We identified that mammalian phosphoglycolate phosphatase, with an uncertain function, acts in fact as a G3PP. We found that G3PP, by controlling Gro3P levels, regulates glycolysis and glucose oxidation, cellular redox and ATP production, gluconeogenesis, glycerolipid synthesis, and fatty acid oxidation in pancreatic islet β-cells and hepatocytes, and that glucose stimulated insulin secretion and the response tometabolic stress, e.g., glucolipotoxicity, in β-cells. In vivo overexpression of G3PP in rat liver lowers body weight gain and hepatic glucose production from glycerol and elevates plasma HDL levels. G3PP is expressed at various levels in different tissues, and its expression varies according to the nutritional state in some tissues. As Gro3P lies at the crossroads of glucose, lipid, and energy metabolism, control of its availability by G3PP adds a key level of metabolic regulation in mammalian cells, and G3PP offers a potential target for type 2 diabetes and cardiometabolic disorders.
AB - Obesity, and the associated disturbed glycerolipid/fatty acid (GL/FA) cycle, contribute to insulin resistance, islet β-cell failure, and type 2 diabetes. Flux through the GL/FA cycle is regulated by the availability of glycerol-3-phosphate (Gro3P) and fatty acyl-CoA. We describe here amammalian Gro3P phosphatase (G3PP), which was not known to exist in mammalian cells, that can directly hydrolyze Gro3P to glycerol. We identified that mammalian phosphoglycolate phosphatase, with an uncertain function, acts in fact as a G3PP. We found that G3PP, by controlling Gro3P levels, regulates glycolysis and glucose oxidation, cellular redox and ATP production, gluconeogenesis, glycerolipid synthesis, and fatty acid oxidation in pancreatic islet β-cells and hepatocytes, and that glucose stimulated insulin secretion and the response tometabolic stress, e.g., glucolipotoxicity, in β-cells. In vivo overexpression of G3PP in rat liver lowers body weight gain and hepatic glucose production from glycerol and elevates plasma HDL levels. G3PP is expressed at various levels in different tissues, and its expression varies according to the nutritional state in some tissues. As Gro3P lies at the crossroads of glucose, lipid, and energy metabolism, control of its availability by G3PP adds a key level of metabolic regulation in mammalian cells, and G3PP offers a potential target for type 2 diabetes and cardiometabolic disorders.
KW - Glucolipotoxicity
KW - Gluconeogenesis
KW - Glucose-stimulated insulin secretion
KW - Glycerol-3-phosphate phosphatase
KW - Type 2 diabetes
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U2 - 10.1073/pnas.1514375113
DO - 10.1073/pnas.1514375113
M3 - Article
C2 - 26755581
AN - SCOPUS:84955594885
SN - 0027-8424
VL - 113
SP - E430-E439
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 4
ER -