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Regulation of liver metabolism by the endosomal GTPase Rab5.

Cell Rep. 2015 May 12;11(6):884-892. Epub 2015 Apr 30
Anja Zeigerer 1 , Roman L Bogorad 2 , Kirti Sharma 3 , Jerome Gilleron 4 , Sarah Seifert 1 , Susanne Sales 1 , Nikolaus Berndt 5 , Sascha Bulik 5 , Giovanni Marsico 6 , Rochelle C J D'Souza 3 , Naharajan Lakshmanaperumal 1 , Kesavan Meganathan 7 , Karthick Natarajan 7 , Agapios Sachinidis 7 , Andreas Dahl 8 , Hermann-Georg Holzhütter 5 , Andrej Shevchenko 1 , Matthias Mann 3 , Victor Koteliansky 9 , Marino Zerial 10
Anja Zeigerer 1 , Roman L Bogorad 2 , Kirti Sharma 3 , Jerome Gilleron 4 , Sarah Seifert 1 , Susanne Sales 1 , Nikolaus Berndt 5 , Sascha Bulik 5 , Giovanni Marsico 6 , Rochelle C J D'Souza 3 , Naharajan Lakshmanaperumal 1 , Kesavan Meganathan 7 , Karthick Natarajan 7 , Agapios Sachinidis 7 , Andreas Dahl 8 , Hermann-Georg Holzhütter 5 , Andrej Shevchenko 1 , Matthias Mann 3 , Victor Koteliansky 9 , Marino Zerial 10
+ et al

[No authors listed]

Author information
  • 1 Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
  • 2 David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
  • 3 Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
  • 4 INSERM U1065, Centre Méditerranéen de Médecine Moléculaire C3M, Université de Nice Sophia-Antipolis, 06108 Nice, France.
  • 5 Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
  • 6 Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
  • 7 University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany.
  • 8 Deep Sequencing Group SFB655, BIOTEC, Technical University Dresden, 01307 Dresden, Germany.
  • 9 Skolkovo Institute of Science and Technology, ul. Novaya, d.100, Skolkovo 143025, Russian Federation; Lomonosov Moscow State University, Chemistry Department, Leninskie, Gory, 1/3, Moscow 119991, Russian Federation.
  • 10 Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany. Electronic address: zerial@mpi-cbg.de.

摘要


The liver maintains glucose and lipid homeostasis by adapting its metabolic activity to the energy needs of the organism. Communication between hepatocytes and extracellular environment via endocytosis is key to such homeostasis. Here, we addressed the question of whether endosomes are required for gluconeogenic gene expression. We took advantage of the loss of endosomes in the mouse liver upon Rab5 silencing. Strikingly, we found hepatomegaly and severe metabolic defects such as hypoglycemia, hypercholesterolemia, hyperlipidemia, and glycogen accumulation that phenocopied those found in von Gierke's disease, a glucose-6-phosphatase (G6Pase) deficiency. G6Pase deficiency alone can account for the reduction in hepatic glucose output and glycogen accumulation as determined by mathematical modeling. Interestingly, we uncovered functional alterations in the transcription factors, which regulate G6Pase expression. Our data highlight a requirement of Rab5 and the endosomal system for the regulation of gluconeogenic gene expression that has important implications for metabolic diseases.