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.

非酒精性脂肪肝疾病（NAFLD）代表与肥胖相关的2型糖尿病的关键特征，在世界范围内患病率呈上升趋势。据我们所知，迄今为止尚无可用的治疗方法，这为更严重的肝损伤（包括肝硬化和肝细胞癌）铺平了道路。在这里，我们在线粒体裂变和激活中显示了细胞内运输调节剂小Rab GTPase Rab24的意外功能，这对肝和全身能量稳态具有直接影响。在肥胖的NAFLD患者的肝脏中，RAB24高度上调，并且与人体脂肪增加呈正相关。肝选择性抑制Rab24会增加自噬通量和线粒体连通性，导致肥胖小鼠肝脂肪变性明显改善，血清葡萄糖和胆固醇水平降低。我们的研究突出了运输调节剂（如RAB24）对NAFLD的潜在治疗应用，并建立了细胞内转运与系统性代谢功能障碍之间的概念性功能联系。