Hepatic Rab24 controls blood glucose homeostasis via improving mitochondrial plasticity

Nat Metab. 2019 Oct;1(10):1009-1026. doi: 10.1038/s42255-019-0124-x. Epub 2019 Oct 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Blood Glucose
  • Cholesterol
  • Rab24 protein, mouse
  • RAB24 protein, human
  • rab GTP-Binding Proteins