GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity

Yumeng Peng, Qiang Zeng, Luming Wan, Enhao Ma, Huilong Li, Xiaopan Yang, Yanhong Zhang, Linfei Huang, Haotian Lin, Jiangyue Feng, Yixin Xu, Jingfei Li, Muyi Liu, Jing Liu, Changqin Lin, Zhiwei Sun, Gong Cheng, Xuemiao Zhang, Jialong Liu, Dongrui Li, Meng Wei, Yunhai Mo, Xuetao Mu, Xiaowei Deng, Dandan Zhang, Siqing Dong, Hanqing Huang, Yi Fang, Qi Gao, Xiaoli Yang, Feixiang Wu, Hui Zhong and Congwen Wei ()
Additional contact information
Yumeng Peng: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Qiang Zeng: Health management Institute, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital
Luming Wan: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Enhao Ma: Tsinghua University
Huilong Li: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Xiaopan Yang: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Yanhong Zhang: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Linfei Huang: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Haotian Lin: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Jiangyue Feng: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Yixin Xu: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Jingfei Li: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Muyi Liu: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Jing Liu: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Changqin Lin: Beijing Sungen Biomedical Technology Co., Ltd.
Zhiwei Sun: Beijing Sungen Biomedical Technology Co., Ltd.
Gong Cheng: Tsinghua University
Xuemiao Zhang: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Jialong Liu: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Dongrui Li: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Meng Wei: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Yunhai Mo: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Xuetao Mu: Chinese PLA General Hospital
Xiaowei Deng: Chinese PLA General Hospital
Dandan Zhang: Chinese PLA General Hospital
Siqing Dong: Chinese PLA General Hospital
Hanqing Huang: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Yi Fang: Chinese PLA General Hospital
Qi Gao: Beijing Sungen Biomedical Technology Co., Ltd.
Xiaoli Yang: Chinese PLA General Hospital
Feixiang Wu: Affiliated Tumor Hospital of Guangxi Medical University
Hui Zhong: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
Congwen Wei: Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-27309-1

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