title: Identification of a mammalian glycerol-3-phosphate phosphatase: Role in metabolism and signaling in pancreatic β-cells and hepatocytes.
abstract: 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 a mammalian 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 to metabolic 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.
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada;
authors.forename: Yves
authors.initials: Y
authors.lastname: Mugabo
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada;
authors.forename: Shangang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Institute for Pharmacology and Toxicology and Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg 97080, Germany;
authors.forename: Annegrit
authors.initials: A
authors.lastname: Seifried
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada;
authors.forename: Sari
authors.initials: S
authors.lastname: Gezzar
authors.affiliation: Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada; Department of Experimental Medicine, McGill University, Montréal, QC H3A 0G1, Canada.
authors.forename: Anfal
authors.initials: A
authors.lastname: Al-Mass
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada;
authors.forename: Dongwei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada;
authors.forename: Julien
authors.initials: J
authors.lastname: Lamontagne
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada;
authors.forename: Camille
authors.initials: C
authors.lastname: Attane
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada;
authors.forename: Pegah
authors.initials: P
authors.lastname: Poursharifi
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada;
authors.forename: José
authors.initials: J
authors.lastname: Iglesias
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada;
authors.forename: Erik
authors.initials: E
authors.lastname: Joly
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada;
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Peyot
authors.affiliation: Institute for Pharmacology and Toxicology and Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg 97080, Germany;
authors.forename: Antje
authors.initials: A
authors.lastname: Gohla
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada; murthy.madiraju@crchum.qc.ca marc.prentki@umontreal.ca.
authors.forename: S R Murthy
authors.initials: SR
authors.lastname: Madiraju
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H1W 4A4, Canada; murthy.madiraju@crchum.qc.ca marc.prentki@umontreal.ca.
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D050260:Carbohydrate Metabolism / Q000502:physiology*; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D005994:Glycerophosphates / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology*; D006868:Hydrolysis; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009752:Nutritional Status; D000077403:Orlistat; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology
chemical_list: D005227:Fatty Acids; D005994:Glycerophosphates; D007328:Insulin; D007783:Lactones; D024101:Mitochondrial Proteins; D000077403:Orlistat; C029620:alpha-glycerophosphoric acid; C022408:phosphoglycolate phosphatase; D010744:Phosphoric Monoester Hydrolases; D005990:Glycerol
keywords: glucolipotoxicity; gluconeogenesis; glucose-stimulated insulin secretion; glycerol-3-phosphate phosphatase; type 2 diabetes