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Research Article

Identification of a mammalian glycerol-3-phosphate phosphatase: Role in metabolism and signaling in pancreatic β-cells and hepatocytes

Yves Mugabo, Shangang Zhao, Annegrit Seifried, Sari Gezzar, Anfal Al-Mass, Dongwei Zhang, Julien Lamontagne, Camille Attane, Pegah Poursharifi, José Iglesias, Erik Joly, Marie-Line Peyot, Antje Gohla, S. R. Murthy Madiraju, and Marc Prentki
  1. aDepartments 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;
  2. bInstitute for Pharmacology and Toxicology and Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg 97080, Germany;
  3. cMontreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, QC H1W 4A4, Canada;
  4. dDepartment of Experimental Medicine, McGill University, Montréal, QC H3A 0G1, Canada

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PNAS January 26, 2016 113 (4) E430-E439; first published January 11, 2016; https://doi.org/10.1073/pnas.1514375113
Yves Mugabo
aDepartments 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;
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Shangang Zhao
aDepartments 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;
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Annegrit Seifried
bInstitute for Pharmacology and Toxicology and Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg 97080, Germany;
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Sari Gezzar
aDepartments 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;
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Anfal Al-Mass
cMontreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, QC H1W 4A4, Canada;
dDepartment of Experimental Medicine, McGill University, Montréal, QC H3A 0G1, Canada
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Dongwei Zhang
aDepartments 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;
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Julien Lamontagne
aDepartments 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;
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Camille Attane
aDepartments 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;
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Pegah Poursharifi
aDepartments 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;
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José Iglesias
aDepartments 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;
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Erik Joly
aDepartments 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;
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Marie-Line Peyot
aDepartments 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;
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Antje Gohla
bInstitute for Pharmacology and Toxicology and Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg 97080, Germany;
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S. R. Murthy Madiraju
aDepartments 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;
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  • For correspondence: murthy.madiraju@crchum.qc.ca marc.prentki@umontreal.ca
Marc Prentki
aDepartments 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;
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  • For correspondence: murthy.madiraju@crchum.qc.ca marc.prentki@umontreal.ca
  1. Edited by John H. Exton, Vanderbilt University School of Medicine, Nashville, TN, and approved December 11, 2015 (received for review July 21, 2015)

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Significance

Glycerol-3-phosphate (Gro3P) lies at the crossroads of glucose, lipid, and energy metabolism in mammalian cells and is thought to participate in glycolysis or in gluconeogenesis, lipid synthesis, and Gro3P electron transfer shuttle to mitochondria. We now report a previously unidentified pathway of Gro3P metabolism in mammalian cells with the identification of Gro3P phosphatase (G3PP) that can directly hydrolyze Gro3P to glycerol. We observed that G3PP expression level controls glycolysis, lipogenesis, lipolysis, fatty acid oxidation, cellular redox, and mitochondrial energy metabolism in β-cells and hepatocytes, as well as glucose-induced insulin secretion and the response to metabolic stress in β-cells, and in gluconeogenesis in hepatocytes. G3PP is a previously unknown player in metabolic regulation and signaling and offers a potential target for cardiometabolic disorders.

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.

  • glycerol-3-phosphate phosphatase
  • gluconeogenesis
  • glucolipotoxicity
  • type 2 diabetes
  • glucose-stimulated insulin secretion

Footnotes

  • ↵1Y.M. and S.Z. contributed equally to this work.

  • ↵2Present address: Diabetes Research Center, Beijing University of Chinese Medicine, Beijing 100029, China.

  • ↵3Present address: Departamento de Nutricion y Bioquímica, Pontificia Universidad Javeriana, Cra 7, No 43-82, Edf. Carlos Ortiz, Bogotá, Colombia.

  • ↵4To whom correspondence may be addressed. Email: murthy.madiraju{at}crchum.qc.ca or marc.prentki{at}umontreal.ca.
  • Author contributions: S.R.M.M. and M.P. designed research; Y.M., S.Z., A.S., S.G., A.A.-M., D.Z., J.L., C.A., P.P., J.I., S.R.M.M., and M.P. performed research; A.S. and A.G. contributed new reagents/analytic tools; Y.M., E.J., M.-L.P., S.R.M.M., and M.P. analyzed data; and Y.M., S.R.M.M., and M.P. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1514375113/-/DCSupplemental.

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A mammalian glycerol-3-phosphate phosphatase
Yves Mugabo, Shangang Zhao, Annegrit Seifried, Sari Gezzar, Anfal Al-Mass, Dongwei Zhang, Julien Lamontagne, Camille Attane, Pegah Poursharifi, José Iglesias, Erik Joly, Marie-Line Peyot, Antje Gohla, S. R. Murthy Madiraju, Marc Prentki
Proceedings of the National Academy of Sciences Jan 2016, 113 (4) E430-E439; DOI: 10.1073/pnas.1514375113

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A mammalian glycerol-3-phosphate phosphatase
Yves Mugabo, Shangang Zhao, Annegrit Seifried, Sari Gezzar, Anfal Al-Mass, Dongwei Zhang, Julien Lamontagne, Camille Attane, Pegah Poursharifi, José Iglesias, Erik Joly, Marie-Line Peyot, Antje Gohla, S. R. Murthy Madiraju, Marc Prentki
Proceedings of the National Academy of Sciences Jan 2016, 113 (4) E430-E439; DOI: 10.1073/pnas.1514375113
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