Hepatic Rab24 controls blood glucose homeostasis via improving mitochondrial plasticity.

Susanne Seitz,Revathi Sekar,Natalie Krahmer,Kerstin Stemmer,Matthias Blüher,Anne Loft,Bahar Najafi,Sofiya Gancheva,Annette Feuchtinger,Michael Roden,Anja Zeigerer,Christian Behrends,Stephan Herzig,Matthias Mann,Julia Jülg,Timo Müller ,Yongseok Kwon ,Martin Hrabě De Angelis ,Goetz Hartleben ,Jérôme Gilleron ,Mauricio Berriel Díaz

doi:10.1038/s42255-019-0124-x

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.

Highlights

Intracellular transport controls the internalization of nutrients into cells, the finetuning and downregulation of signaling receptors and the packaging and secretion of proteins, lipids and other metabolites[1,2,3,4,5,6]
We show an unexpected function for an intracellular trafficking regulator, the small Rab GTPase Rab[24], in mitochondrial fission and activation with immediate impact on hepatic and systemic energy homeostasis
RAB24 is highly upregulated in livers of obese Non-alcoholic fatty liver disease (NAFLD) patients and positively correlates with increased body fat in humans

Summary

Introduction

Intracellular transport controls the internalization of nutrients into cells, the finetuning and downregulation of signaling receptors and the packaging and secretion of proteins, lipids and other metabolites[1,2,3,4,5,6]. These functions are mediated via vesicular trafficking, which is controlled by coat proteins, SNAREs and Rab GTPases that collectively enable the specificity in the intracellular distribution of cargoes[4,6,7,8,9]. Hundreds of trafficking components are involved in intracellular transport, providing a large population of potential metabolic regulators waiting to be characterized

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Conclusion