PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis

Yong-Sheng Cheng; Oksana Seibert; Nora Klöting; Arne Dietrich; Katrin Straßburger; Sonia Fernández-Veledo; Joan J Vendrell; Antonio Zorzano; Matthias Blüher; Stephan Herzig; Mauricio Berriel Diaz; Aurelio A Teleman

doi:10.1371/journal.pgen.1005561

PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis

PLoS Genet. 2015 Oct 6;11(10):e1005561. doi: 10.1371/journal.pgen.1005561. eCollection 2015 Oct.

Affiliations

¹ German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Department of Medicine, University of Leipzig, Leipzig, Germany.
³ Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili. Universitat, Rovira i Virgili, CIBERDEM, Tarragona, Spain.
⁴ Hospital Universitari de Tarragona Joan XXIII. Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgili, CIBERDEM, Tarragona, Spain.
⁵ Institute for Research in Biomedicine (IRB Barcelona), Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, and CIBERDEM, Barcelona, , Spain.
⁶ 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.
⁷ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / genetics
Animals
Dietary Carbohydrates / metabolism
Energy Metabolism / genetics*
Glucose / metabolism
Hepatocytes / metabolism
Humans
Insulin Resistance / genetics
Lipid Metabolism / genetics*
Lipogenesis / genetics
Liver / metabolism
Mice
Obesity / genetics*
Obesity / pathology
Protein Phosphatase 2 / genetics*
Sterol Regulatory Element Binding Protein 1 / genetics

Substances

Dietary Carbohydrates
SREBF1 protein, human
Sterol Regulatory Element Binding Protein 1
AMP-Activated Protein Kinases
PPP2R5C protein, human
Protein Phosphatase 2
Glucose

Grants and funding

This work was supported in part by a Fritz Thyssen Stiftung grant (10.10.2.158) to AAT, a Deutsche Forschungsgemeinschaft grant (He3260/4-2) to SH, a joint Helmholtz Portfolio Topic grant “Metabolic Dysfunction” to SH and AAT, and the SFB 1118 funded by the Deutsche Forschungsgemeinschaft. The Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM) (CB07708/0012) is an initiative of the Instituto de Salud Carlos III. SFV acknowledges support from the “Miguel Servet” tenure-track program (CP10/00438) from the Fondo de Investigación Sanitaria (FIS) co-financed by the European Regional Development Fund (ERDF) and from from the Spanish Ministry of Economy and Competitiveness (SAF2012-36186). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.