Regulation of liver metabolism by the endosomal GTPase Rab5.
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.
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Anja
A
Zeigerer
David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
Roman L
RL
Bogorad
Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
Kirti
K
Sharma
INSERM U1065, Centre Méditerranéen de Médecine Moléculaire C3M, Université de Nice Sophia-Antipolis, 06108 Nice, France.
Jerome
J
Gilleron
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Sarah
S
Seifert
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Susanne
S
Sales
Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Nikolaus
N
Berndt
Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Sascha
S
Bulik
Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
Giovanni
G
Marsico
Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
Rochelle C J
RCJ
D'Souza
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Naharajan
N
Lakshmanaperumal
University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany.
Kesavan
K
Meganathan
University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany.
Karthick
K
Natarajan
University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany.
Agapios
A
Sachinidis
Deep Sequencing Group SFB655, BIOTEC, Technical University Dresden, 01307 Dresden, Germany.
Andreas
A
Dahl
Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Hermann-Georg
HG
Holzhütter
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Andrej
A
Shevchenko
Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
Matthias
M
Mann
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.
Victor
V
Koteliansky
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany. Electronic address: zerial@mpi-cbg.de.
Marino
M
Zerial
D000818:Animals; D003198:Computer Simulation; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000473:pathology; D011992:Endosomes / Q000201:enzymology*; D055785:Gene Knockdown Techniques; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000201:enzymology / Q000473:pathology; D006529:Hepatomegaly / Q000201:enzymology / Q000473:pathology; D006943:Hyperglycemia / Q000201:enzymology / Q000473:pathology; D007003:Hypoglycemia / Q000201:enzymology / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology*; D018345:Mice, Knockout; D008954:Models, Biological; D040901:Proteomics; D015398:Signal Transduction / Q000235:genetics; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
D007328:Insulin; D006003:Glycogen; D005952:Glucose-6-Phosphatase; D020696:rab5 GTP-Binding Proteins; D005947:Glucose