Nature communications · 2021
GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity.
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Peng Yumeng, Zeng Qiang, Wan Luming, Ma Enhao, Li Huilong, Yang Xiaopan, Zhang Yanhong, Huang Linfei, Lin Haotian, Feng Jiangyue, Xu Yixin, Li Jingfei, Liu Muyi, Liu Jing, Lin Changqin, Sun Zhiwei, Cheng Gong, Zhang Xuemiao, Liu Jialong, Li Dongrui, Wei Meng, Mo Yunhai, Mu Xuetao, Deng Xiaowei, Zhang Dandan, Dong Siqing, Huang Hanqing, Fang Yi, Gao Qi, Yang Xiaoli, Wu Feixiang, Zhong Hui, Wei Congwen
Аннотация
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.