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.

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your

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SIMILAR CONTENT BEING VIEWED BY OTHERS THE E3 UBIQUITIN-PROTEIN LIGASE TRIM31 ALLEVIATES NON-ALCOHOLIC FATTY LIVER DISEASE BY TARGETING RHBDF2 IN MOUSE HEPATOCYTES Article Open access 25

February 2022 LIVER LIPOPHAGY AMELIORATES NONALCOHOLIC STEATOHEPATITIS THROUGH EXTRACELLULAR LIPID SECRETION Article Open access 13 July 2023 LYSOSOMAL-ASSOCIATED PROTEIN TRANSMEMBRANE 5

AMELIORATES NON-ALCOHOLIC STEATOHEPATITIS BY PROMOTING THE DEGRADATION OF CDC42 IN MICE Article Open access 08 May 2023 ACCESSION CODES PRIMARY ACCESSIONS GENE EXPRESSION OMNIBUS * GSE87389

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Article  CAS  PubMed  Google Scholar  Download references 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.). AUTHOR INFORMATION Author notes * Guang-Nian Zhao,

Peng Zhang, Jun Gong and Xiao-Jing Zhang: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Medical Science Research Center, Zhongnan Hospital of Wuhan University,

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

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 * 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 * College of Life Sciences, Wuhan University, Wuhan, China Guang-Nian Zhao, Jun Gong, Zhou Jiang, Jingjing

Tong, Xin Zhang & Zan Huang * 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 * 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 * Biomedical Engineering Department, Huazhong University of Science and

Technology, Wuhan, China Qingguo Xie Authors * Guang-Nian Zhao View author publications You can also search for this author inPubMed Google Scholar * Peng Zhang View author publications You

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author publications You can also search for this author inPubMed Google Scholar * Zhou Jiang View author publications You can also search for this author inPubMed Google Scholar * Li-Jun

Shen View author publications You can also search for this author inPubMed Google Scholar * Yan-Xiao Ji View author publications You can also search for this author inPubMed Google Scholar *

Jingjing Tong View author publications You can also search for this author inPubMed Google Scholar * Yutao Wang View author publications You can also search for this author inPubMed Google

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 Google Scholar * Xue-Yong Zhu View author publications You can also search for this author inPubMed Google Scholar * Xin Zhang View author publications You can also search for this author

inPubMed Google Scholar * Jing Fang View author publications You can also search for this author inPubMed Google Scholar * Qingguo Xie View author publications You can also search for this

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search for this author inPubMed Google Scholar 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.

CORRESPONDING AUTHOR Correspondence to Hongliang Li. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY

FIGURES AND TABLES 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)

RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation *

Received: 02 October 2016 * Accepted: 07 April 2017 * Published: 08 May 2017 * Issue Date: June 2017 * DOI: https://doi.org/10.1038/nm.4334 SHARE THIS ARTICLE Anyone you share the following

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