Hepatic Rab24 controls blood glucose homeostasis via improving mitochondrial plasticity
Authors: Matthias Blüher
Götz Hartleben
Susanne Seitz
Bahar Najafi
Christian Behrends
Kerstin Stemmer
Yun Kwon
Anne Loft
Annette Feuchtinger
Revathi Sekar
Martin Hrabe de Angelis
Natalie Krahmer
Michael Roden
Mauricio Berriel Diaz
Jerome Gilleron
Stephan Herzig
Anja Zeigerer
Julia Jülg
Sofiya Gancheva
Timo D Müller
Matthias Mann
Journal: Nature Metabolism (2019)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Non-alcoholic fatty liver disease; NAFLD; obesity-related type 2 diabetes; treatment options; liver damage
Affiliations: Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany., German Center for Diabetes Research, Neuherberg, Germany., Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany., Munich Cluster for Systems Neurology, Ludwig-Maximilians-University München, Munich, Germany., Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany., Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany., Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany., Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany., Research Unit Analytical Pathology, Helmholtz Center Munich, Neuherberg, Germany., Institute of Experimental Genetics, Helmholtz Center Munich German Research Center for Environmental Health, Neuherberg, Germany., Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany., Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany., NF Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark., Department of Medicine, University of Leipzig, Leipzig, Germany., Université Côte d'Azur, Institut National de la Santé et de la Recherche Médicale UMR1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France., Chair Molecular Metabolic Control, Technical University Munich, Munich, Germany., Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany. ., German Center for Diabetes Research, Neuherberg, Germany. ., Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany. .

Abstract:  Non-alcoholic fatty liver disease (NAFLD) represents a key feature of obesity-related type 2 diabetes with increasing prevalence worldwide. To our knowledge, no treatment options are available to date, paving the way for more severe liver damage, including cirrhosis and hepatocellular carcinoma. Here, we show an unexpected function for an intracellular trafficking regulator, the small Rab GTPase Rab24, in mitochondrial fission and activation, which has an immediate impact on hepatic and systemic energy homeostasis. RAB24 is highly upregulated in the livers of obese patients with NAFLD and positively correlates with increased body fat in humans. Liver-selective inhibition of Rab24 increases autophagic flux and mitochondrial connectivity, leading to a strong improvement in hepatic steatosis and a reduction in serum glucose and cholesterol levels in obese mice. Our study highlights a potential therapeutic application of trafficking regulators, such as RAB24, for NAFLD and establishes a conceptual functional connection between intracellular transport and systemic metabolic dysfunction. 

Retracted: No

PubPeer comments:
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