The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulating ApoB export. Upon regular-diet feeding, liver-GP73-high mice display non-obese NAFLD phenotype, characterized by reduced body weight, intrahepatic lipid accumulation, and gradual insulin resistance development, none of which can be recapitulated in liver-GAP inactive GP73-high mice. Common and specific gene expression signatures associated with GP73-induced non-obese NAFLD and high-fat diet (HFD)-induced obese NAFLD are revealed. Notably, metformin inactivates the GAP activity of GP73 and alleviates GP73-induced non-obese NAFLD. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. These findings reveal a pathophysiological role of GP73 in triggering non-obese NAFLD and may offer an opportunity for clinical intervention.

非肥胖非酒精性脂肪性肝病 (NAFLD) 的患病率在世界范围内不断增加，病因和发病机制尚不清楚。在这里，我们展示了 GP73，一种在患有各种肝病的患者的肝脏中上调的高尔基体蛋白，表现出调节 ApoB 输出的 Rab GTP 酶激活蛋白 (GAP) 活性。在定期饮食喂养后，肝 GP73-high 小鼠表现出非肥胖 NAFLD 表型，其特征是体重减轻、肝内脂质积累和胰岛素抵抗逐渐发展，这些都不能在肝-GAP 失活的 GP73-high 小鼠中重现. 揭示了与 GP73 诱导的非肥胖 NAFLD 和高脂肪饮食 (HFD) 诱导的肥胖 NAFLD 相关的常见和特定基因表达特征。值得注意的是，二甲双胍使 GP73 的 GAP 活性失活并减轻 GP73 诱导的非肥胖 NAFLD。GP73 在非肥胖 NAFLD 个体中病理性升高，GP73 阻断可改善非肥胖 NAFLD 小鼠模型的全身代谢。这些发现揭示了 GP73 在触发非肥胖 NAFLD 中的病理生理作用，并可能为临床干预提供机会。