Hepatic Rab24 controls blood glucose homeostasis via improving mitochondrial plasticity

Susanne Seitz, Yun Kwon, Götz Hartleben, Julia Jülg, Revathi Sekar, Natalie Krahmer, Bahar Najafi, Anne Loft, Sofiya Gancheva, Kerstin Stemmer, Annette Feuchtinger, Martin Hrabe de Angelis, Timo D. Müller, Matthias Mann, Matthias Blüher, Michael Roden, Mauricio Berriel Diaz, Christian Behrends, Jerome Gilleron, Stephan HerzigAnja Zeigerer

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish
Pages (from-to)1009-1026
Number of pages18
JournalNature Metabolism
Volume1
Issue number10
DOIs
StatePublished - 1 Oct 2019

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