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Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4

Nature Medicine volume 23, pages 742–752 (2017)Cite this article

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Abstract

Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent liver pathology that can progress from non-alcoholic fatty liver disease (NAFLD), and it is a leading cause of cirrhosis and hepatocellular carcinoma. There is currently no pharmacological therapy for NASH. Defective lysosome-mediated protein degradation is a key process that underlies steatohepatitis and a well-recognized drug target in a variety of diseases; however, whether it can serve as a therapeutic target for NAFLD and NASH remains unknown. Here we report that transmembrane BAX inhibitor motif-containing 1 (TMBIM1) is an effective suppressor of steatohepatitis and a previously unknown regulator of the multivesicular body (MVB)-lysosomal pathway. Tmbim1 expression in hepatocytes substantially inhibited high-fat diet–induced insulin resistance, hepatic steatosis and inflammation in mice. Mechanistically, Tmbim1 promoted the lysosomal degradation of toll-like receptor 4 by cooperating with the ESCRT endosomal sorting complex to facilitate MVB formation, and the ubiquitination of Tmbim1 by the E3 ubiquitin ligase Nedd4l was required for this process. We also found that overexpression of Tmbim1 in the liver effectively inhibited a severe form of NAFLD in mice and NASH progression in monkeys. Taken together, these findings could lead to the development of promising strategies to treat NASH by targeting MVB regulators to properly orchestrate the lysosome-mediated protein degradation of key mediators of the disease.

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Figure 1: Correlation of Tmbim1 expression with fatty liver diseases.
Figure 2: Tmbim1 deletion exacerbates insulin resistance, hepatic steatosis and inflammation.
Figure 3: Tlr4 signaling is required for Tmbim1 function.
Figure 4: TMBIM1 promotes the lysosomal degradation of TLR4 by facilitating MVB formation.
Figure 5: The physiological function of Tmbim1 is dependent on its ubiquitination.
Figure 6: TMBIM1 ameliorates metabolic syndromes and hepatic steatosis in monkeys.

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Acknowledgements

We appreciate L. Wan and J. Li (Huazhong University of Science and Technology) for PET operation. We thank L. Ma (Wuhan University), a biostatistics expert, for his help with our statistical analyses. This work was supported by the National Science Fund for Distinguished Young Scholars (grant no. 81425005; H.L.), the National Natural Science Foundation (grant no. 81330005 (H.L.), 81630011 (H.L.) and 91329000 (H.L.)), National Science and Technology Support Project no. 2014BAI02B01 (H.L.) and 2015BAI08B01 (H.L.), and National Key Research and Development Program no. 2013YQ030923-05 (H.L.) and 2016YFF0101504 (Z.-G.S.).

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  1. Guang-Nian Zhao, Peng Zhang, Jun Gong and Xiao-Jing Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China

    Guang-Nian Zhao, Peng Zhang, Yan-Xiao Ji & Hongliang Li

  2. Basic Medical School, Wuhan University, Wuhan, China

    Guang-Nian Zhao, Peng Zhang, Jun Gong, Xiao-Jing Zhang, Pi-Xiao Wang, Miao Yin, Zhou Jiang, Li-Jun Shen, Yan-Xiao Ji, Jingjing Tong, Yutao Wang, Qiao-Fang Wei, Xue-Yong Zhu, Xin Zhang, Zhi-Gang She, Zhihua Wang, Zan Huang & Hongliang Li

  3. Institute of Model Animal of Wuhan University, Wuhan, China

    Guang-Nian Zhao, Peng Zhang, Jun Gong, Xiao-Jing Zhang, Pi-Xiao Wang, Miao Yin, Zhou Jiang, Li-Jun Shen, Yan-Xiao Ji, Jingjing Tong, Yutao Wang, Qiao-Fang Wei, Yong Wang, Xue-Yong Zhu, Xin Zhang, Zhi-Gang She, Zhihua Wang, Zan Huang & Hongliang Li

  4. Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China

    Guang-Nian Zhao, Peng Zhang, Jun Gong, Xiao-Jing Zhang, Pi-Xiao Wang, Miao Yin, Zhou Jiang, Li-Jun Shen, Yan-Xiao Ji, Jingjing Tong, Yutao Wang, Qiao-Fang Wei, Xue-Yong Zhu, Xin Zhang, Zhi-Gang She, Zhihua Wang, Zan Huang & Hongliang Li

  5. College of Life Sciences, Wuhan University, Wuhan, China

    Guang-Nian Zhao, Jun Gong, Zhou Jiang, Jingjing Tong, Xin Zhang & Zan Huang

  6. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China

    Xiao-Jing Zhang, Pi-Xiao Wang, Li-Jun Shen, Jingjing Tong, Yutao Wang, Qiao-Fang Wei, Zhi-Gang She, Zhihua Wang & Hongliang Li

  7. Division of Cardiothoracic and Vascular Surgery, Heart–Lung Transplantation Center, Sino-Swiss Heart–Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Jing Fang

  8. Biomedical Engineering Department, Huazhong University of Science and Technology, Wuhan, China

    Qingguo Xie

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  1. Guang-Nian Zhao
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Contributions

G.-N.Z., P.Z., J.G. and X.-J.Z. designed and performed experiments, analyzed data and wrote the manuscript; P.-X.W., M.Y., Z.J., Y.-X.J., J.T. and Yutao Wang performed experiments, analyzed data and provided useful advice on the manuscript; J.F. and Yong Wang performed the monkey experiments; X.-Y.Z. performed the western blot experiments; X.Z. constructed the genetically engineered mice used here; L.-J.S. and Q.-F.W. established the mouse models of severe NAFLD and performed mouse experiments; Q.X. performed the PET experiments; Z.-G.S., Z.W. and Z.H. helped design the project and edited the manuscript; and H.L. designed and supervised the experiments and wrote the manuscript.

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Correspondence to Hongliang Li.

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Supplementary Figures 1–25 and Supplementary Tables 1–4 (PDF 7027 kb)

Supplementary Table 5

Identified proteins interacting with TMBIM1 by mass spectrometry (XLSX 12 kb)

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Zhao, GN., Zhang, P., Gong, J. et al. Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4. Nat Med 23, 742–752 (2017). https://doi.org/10.1038/nm.4334

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