Hepatic Rab24 controls blood glucose homeostasis via improving mitochondrial plasticity.

Adiposity Adult Animals Autophagy Blood Glucose / metabolism Cholesterol / blood Female Homeostasis Humans Lipid Metabolism / genetics Male Mice Mice, Inbred C57BL Mice, Knockout Mitochondria, Liver / metabolism Non-alcoholic Fatty Liver Disease / metabolism Obesity / metabolism Up-Regulation rab GTP-Binding Proteins / genetics

Journal

Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592

Informations de publication

Date de publication:
10 2019
Historique:
received: 29 08 2018
accepted: 10 09 2019
entrez: 23 7 2020
pubmed: 23 7 2020
medline: 1 1 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s42255-019-0124-x PMID: 32694843
pubmed: 32694843
doi: 10.1038/s42255-019-0124-x
pii: 10.1038/s42255-019-0124-x
doi:

Substances chimiques

Blood Glucose 0
Cholesterol 97C5T2UQ7J
Rab24 protein, mouse EC 3.6.1-
RAB24 protein, human EC 3.6.1.-
rab GTP-Binding Proteins EC 3.6.5.2

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

1009-1026

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Auteurs

Susanne Seitz (S)

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.

Yun Kwon (Y)

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.

Götz Hartleben (G)

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.

Julia Jülg (J)

Munich Cluster for Systems Neurology, Ludwig-Maximilians-University München, Munich, Germany.

Revathi Sekar (R)

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.

Natalie Krahmer (N)

German Center for Diabetes Research, Neuherberg, Germany.
Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany.

Bahar Najafi (B)

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.

Anne Loft (A)

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.

Sofiya Gancheva (S)

German Center for Diabetes Research, 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.

Kerstin Stemmer (K)

German Center for Diabetes Research, Neuherberg, Germany.
Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany.

Annette Feuchtinger (A)

Research Unit Analytical Pathology, Helmholtz Center Munich, Neuherberg, Germany.

Martin Hrabe de Angelis (M)

German Center for Diabetes Research, 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.
ORCID: 0000-0002-7898-2353

Timo D Müller (TD)

German Center for Diabetes Research, Neuherberg, Germany.
Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany.
Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany.

Matthias Mann (M)

Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
NF Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
ORCID: 0000-0003-1292-4799

Matthias Blüher (M)

Department of Medicine, University of Leipzig, Leipzig, Germany.

Michael Roden (M)

German Center for Diabetes Research, 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.
ORCID: 0000-0001-8200-6382

Mauricio Berriel Diaz (M)

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.

Christian Behrends (C)

Munich Cluster for Systems Neurology, Ludwig-Maximilians-University München, Munich, Germany.
ORCID: 0000-0002-9184-7607

Jerome Gilleron (J)

Université Côte d'Azur, Institut National de la Santé et de la Recherche Médicale UMR1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France.

Stephan Herzig (S)

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.
Chair Molecular Metabolic Control, Technical University Munich, Munich, Germany.

Anja Zeigerer (A)

Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany. anja.zeigerer@helmholtz-muenchen.de.
German Center for Diabetes Research, Neuherberg, Germany. anja.zeigerer@helmholtz-muenchen.de.
Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany. anja.zeigerer@helmholtz-muenchen.de.
ORCID: 0000-0003-4072-0566

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Classifications MeSH

questionsmedicales.fr › Phénomènes physiologiques › Constitution physique › Composition corporelle › Répartition du tissu adipeux › Adiposité › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Eucaryotes › Animaux › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Autophagie › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Glucides › Sucres › Oses › Hexose › Glucose › Glycémie › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Lipides › Lipides membranaires › Stérols › Cholestérol › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Phénomènes physiologiques › Homéostasie › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Métabolisme › Métabolisme lipidique › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Mitochondries › Mitochondries du foie › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Stéatose hépatique › Stéatose hépatique non alcoolique › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Obésité › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation positive › Hepatic Rab24 controls blood glucose...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines G › Protéines G monomériques › Protéines G rab › Hepatic Rab24 controls blood glucose...