Hepatic Rab24 controls blood glucose homeostasis via improving mitochondrial plasticity.
Susanne SeitzYun KwonGötz HartlebenJulia JülgRevathi SekarNatalie KrahmerBahar NajafiAnne LoftSofiya GanchevaKerstin StemmerAnnette FeuchtingerMartin Hrabě de AngelisTimo D MüllerMatthias MannMatthias BlüherMichael RodenMauricio Berriel DiazChristian BehrendsJerome GilleronStephan HerzigAnja ZeigererPublished in: Nature metabolism (2019)
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.
Keyphrases
- blood glucose
- type diabetes
- oxidative stress
- glycemic control
- metabolic syndrome
- weight loss
- insulin resistance
- cardiovascular disease
- risk factors
- cell death
- adipose tissue
- blood pressure
- machine learning
- drug induced
- reactive oxygen species
- bariatric surgery
- early onset
- multiple sclerosis
- weight gain
- body mass index