title: PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis.
abstract: In mammals, the liver plays a central role in maintaining carbohydrate and lipid homeostasis by acting both as a major source and a major sink of glucose and lipids. In particular, when dietary carbohydrates are in excess, the liver converts them to lipids via de novo lipogenesis. The molecular checkpoints regulating the balance between carbohydrate and lipid homeostasis, however, are not fully understood. Here we identify PPP2R5C, a regulatory subunit of PP2A, as a novel modulator of liver metabolism in postprandial physiology. Inactivation of PPP2R5C in isolated hepatocytes leads to increased glucose uptake and increased de novo lipogenesis. These phenotypes are reiterated in vivo, where hepatocyte specific PPP2R5C knockdown yields mice with improved systemic glucose tolerance and insulin sensitivity, but elevated circulating triglyceride levels. We show that modulation of PPP2R5C levels leads to alterations in AMPK and SREBP-1 activity. We find that hepatic levels of PPP2R5C are elevated in human diabetic patients, and correlate with obesity and insulin resistance in these subjects. In sum, our data suggest that hepatic PPP2R5C represents an important factor in the functional wiring of energy metabolism and the maintenance of a metabolically healthy state.
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Cheng
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Oksana
authors.initials: O
authors.lastname: Seibert
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Klöting
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Dietrich
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Straßburger
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili. Universitat, Rovira i Virgili, CIBERDEM, Tarragona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fernández-Veledo
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII. Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgili, CIBERDEM, Tarragona, Spain.
authors.forename: Joan J
authors.initials: JJ
authors.lastname: Vendrell
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, and CIBERDEM, Barcelona, , Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany, and Joint Heidelberg-IDC Translational Diabetes Program, University Hospital Heidelberg, Heidelberg, Germany; Chair Molecular Metabolic Control, Medical Faculty, Technical University Munich, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany, and Joint Heidelberg-IDC Translational Diabetes Program, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Berriel Diaz
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Aurelio A
authors.initials: AA
authors.lastname: Teleman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics; D000818:Animals; D004040:Dietary Carbohydrates / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D054648:Protein Phosphatase 2 / Q000235:genetics*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics
chemical_list: D004040:Dietary Carbohydrates; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D055372:AMP-Activated Protein Kinases; C503981:PPP2R5C protein, human; D054648:Protein Phosphatase 2; D005947:Glucose