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

Author

Listed:
  • Yumeng Peng

    (Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
    Affiliated Tumor Hospital of Guangxi Medical University)

  • 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)
    Affiliated Tumor Hospital of Guangxi Medical University)

  • 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)
    Affiliated Tumor Hospital of Guangxi Medical University)

  • 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)
    Chinese PLA General Hospital)

  • Jialong Liu

    (Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
    Chinese PLA General Hospital)

  • Dongrui Li

    (Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS))

  • Meng Wei

    (Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
    Affiliated Tumor Hospital of Guangxi Medical University)

  • Yunhai Mo

    (Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)
    Affiliated Tumor Hospital of Guangxi Medical University)

  • 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))

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.

Suggested Citation

  • 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 &, 2021. "GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27309-1
    DOI: 10.1038/s41467-021-27309-1
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    as
    1. Zhuojun Zhang & Chen Zong & Mingyang Jiang & Han Hu & Xiaolei Cheng & Juhua Ni & Xia Yi & Bin Jiang & Feng Tian & Ming-Wen Chang & Wen Su & Lijun Zhu & Jinfan Li & Xueping Xiang & Congxiu Miao & Myria, 2020. "Hepatic HuR modulates lipid homeostasis in response to high-fat diet," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    2. Xiao-Yi Lu & Xiong-Jie Shi & Ao Hu & Ju-Qiong Wang & Yi Ding & Wei Jiang & Ming Sun & Xiaolu Zhao & Jie Luo & Wei Qi & Bao-Liang Song, 2020. "Feeding induces cholesterol biosynthesis via the mTORC1–USP20–HMGCR axis," Nature, Nature, vol. 588(7838), pages 479-484, December.
    3. Giljae Lee & Hyun Ju You & Jasmohan S. Bajaj & Sae Kyung Joo & Junsun Yu & Seoyeon Park & Hyena Kang & Jeong Hwan Park & Jung Ho Kim & Dong Hyeon Lee & Seonhwa Lee & Won Kim & GwangPyo Ko, 2020. "Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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    Cited by:

    1. Zhe Zhang & Xiang Kai Leng & Yuan Yuan Zhai & Xiao Zhang & Zhi Wei Sun & Jun Ying Xiao & Jun Feng Lu & Kun Liu & Bo Xia & Qi Gao & Miao Jia & Cheng Qi Xu & Yi Na Jiang & Xiao Gang Zhang & Kai Shan Tao, 2024. "Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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