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Lysosomal-associated protein transmembrane 5 ameliorates non-alcoholic steatohepatitis by promoting the degradation of CDC42 in mice

Author

Listed:
  • Lang Jiang

    (Huazhong University of Science and Technology)

  • Jing Zhao

    (Huazhong University of Science and Technology)

  • Qin Yang

    (Huanggang Central Hospital)

  • Mei Li

    (Wuhan University)

  • Hao Liu

    (Huazhong University of Science and Technology)

  • Xiaoyue Xiao

    (Huazhong University of Science and Technology)

  • Song Tian

    (Wuhan University)

  • Sha Hu

    (Wuhan University)

  • Zhen Liu

    (Renmin Hospital of Wuhan University)

  • Peiwen Yang

    (Huazhong University of Science and Technology)

  • Manhua Chen

    (Huazhong University of Science and Technology)

  • Ping Ye

    (Huazhong University of Science and Technology)

  • Jiahong Xia

    (Huazhong University of Science and Technology)

Abstract

Non-alcoholic steatohepatitis (NASH) has received great attention due to its high incidence. Here, we show that lysosomal-associated protein transmembrane 5 (LAPTM5) is associated with NASH progression through extensive bioinformatical analysis. The protein level of LAPTM5 bears a negative correlation with NAS score. Moreover, LAPTM5 degradation is mediated through its ubiquitination modification by the E3 ubquitin ligase NEDD4L. Discovered by experiments conducted on male mice, hepatocyte-specific depletion of Laptm5 exacerbates mouse NASH symptoms. In contrast, Laptm5 overexpression in hepatocytes exerts diametrically opposite effects. Mechanistically, LAPTM5 interacts with CDC42 and promotes its degradation through a lysosome-dependent manner under the stimulation of palmitic acid, thus inhibiting activation of the mitogen-activated protein kinase signaling pathway. Finally, adenovirus-mediated hepatic Laptm5 overexpression ameliorates aforementioned symptoms in NASH models.

Suggested Citation

  • Lang Jiang & Jing Zhao & Qin Yang & Mei Li & Hao Liu & Xiaoyue Xiao & Song Tian & Sha Hu & Zhen Liu & Peiwen Yang & Manhua Chen & Ping Ye & Jiahong Xia, 2023. "Lysosomal-associated protein transmembrane 5 ameliorates non-alcoholic steatohepatitis by promoting the degradation of CDC42 in mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37908-9
    DOI: 10.1038/s41467-023-37908-9
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    References listed on IDEAS

    as
    1. Janaki N. Sudhakar & Hsueh-Han Lu & Hung-Yu Chiang & Ching-Shu Suen & Ming-Jing Hwang & Sung-Yu Wu & Chia-Ning Shen & Yao-Ming Chang & Fu-An Li & Fu-Tong Liu & Jr-Wen Shui, 2020. "Lumenal Galectin-9-Lamp2 interaction regulates lysosome and autophagy to prevent pathogenesis in the intestine and pancreas," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    2. Li Zhao & Shumei Wang & Meng Xu & Yang He & Xiaowei Zhang & Ying Xiong & Hong Sun & Haibo Ding & Wenqing Geng & Hong Shang & Guoxin Liang, 2021. "Vpr counteracts the restriction of LAPTM5 to promote HIV-1 infection in macrophages," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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