Hepatic Rab24 controls blood glucose homeostasis via improving mitochondrial plasticity.

Nature Metabolism
Susanne SeitzAnja Zeigerer

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.

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Citations

Nov 7, 2019·Nature Reviews. Endocrinology·Shimona Starling
Mar 15, 2020·Nature Communications·Ruben BoonCatherine M Verfaillie
Jul 3, 2021·International Journal of Molecular Sciences·Siarhei A DabravolskiAlexander N Orekhov
Nov 22, 2020·Molecular Metabolism·Kalliopi Pafili, Michael Roden
Jul 9, 2021·Journal of Medicinal Chemistry·Edyta Gendaszewska-DarmachKatarzyna M Błażewska
Aug 20, 2021·Life Science Alliance·Philip Mm RuppertSander Kersten

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Methods Mentioned

BETA
GTPases
electron microscopy
pulldown
X-ray
enzyme-linked immunosorbent assays
RNA assay
DNA assay
ELISA
reversed-phase chromatography
acetylation

Clinical Trials Mentioned

NCT01477957

Software Mentioned

Andromeda
Fiji Analyze Skeleton
MaxQuant
Axolabs
Image
AnalyzeSkeleton
Skeletonize3D
Ensembl
Fiji
Perseus

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