Tumor Necrosis Factor α–Induced Protein 8–Like 2 Alleviates Nonalcoholic Fatty Liver Disease Through Suppressing Transforming Growth Factor Beta–Activated Kinase 1 Activation
Yupeng Liu
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
These authors contributed equally to this work.Search for more papers by this authorJingjing Song
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
These authors contributed equally to this work.Search for more papers by this authorJuan Yang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
These authors contributed equally to this work.Search for more papers by this authorJilin Zheng
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Search for more papers by this authorLing Yang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
Search for more papers by this authorJun Gao
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Department of Cardiology, The First Hospital of Hebei Medical University, Hebei, China
Search for more papers by this authorSong Tian
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
Search for more papers by this authorZhen Liu
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
Search for more papers by this authorXiangbin Meng
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Department of Cardiology, Zhengzhou University People's Hospital, Central China Fuwai Hospital, Central China Branch of the National Cardiovascular Center, Henan Provincial People's Hospital, Henan, China
Search for more papers by this authorJian-Cheng Wang
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
Search for more papers by this authorZhifei Dai
Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
Search for more papers by this authorCorresponding Author
Yi-Da Tang
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Yi-Da Tang, M.D., Ph.D.
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
No. 49 Huayuanbei Road
100191 Beijing, China
E-mail: [email protected]
Tel.: +86-010-88396171
Search for more papers by this authorYupeng Liu
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
These authors contributed equally to this work.Search for more papers by this authorJingjing Song
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
These authors contributed equally to this work.Search for more papers by this authorJuan Yang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
These authors contributed equally to this work.Search for more papers by this authorJilin Zheng
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Search for more papers by this authorLing Yang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
Search for more papers by this authorJun Gao
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Department of Cardiology, The First Hospital of Hebei Medical University, Hebei, China
Search for more papers by this authorSong Tian
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
Search for more papers by this authorZhen Liu
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
Search for more papers by this authorXiangbin Meng
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Department of Cardiology, Zhengzhou University People's Hospital, Central China Fuwai Hospital, Central China Branch of the National Cardiovascular Center, Henan Provincial People's Hospital, Henan, China
Search for more papers by this authorJian-Cheng Wang
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
Search for more papers by this authorZhifei Dai
Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China
Search for more papers by this authorCorresponding Author
Yi-Da Tang
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Yi-Da Tang, M.D., Ph.D.
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
No. 49 Huayuanbei Road
100191 Beijing, China
E-mail: [email protected]
Tel.: +86-010-88396171
Search for more papers by this authorAbstract
Background and Aims
NAFLD prevalence has increased rapidly and become a major global health problem. Tumor necrosis factor α–induced protein 8–like 2 (TIPE2) plays a protective role in a cluster of liver diseases, such as autoimmune hepatitis, hepatitis B, and hepatocellular carcinoma. However, the function of TIPE2 in NAFLD remains unknown. Here, we investigated the role of TIPE2 in the development of NAFLD.
Approach and Results
Our study found that in vitro overexpression or knockout of TIPE2 significantly ameliorated or aggravated lipid accumulation and inflammation in hepatocytes exposed to metabolic stimulation, respectively. Consistently, in vivo hepatic steatosis, insulin resistance, inflammation, and fibrosis were alleviated in hepatic Tipe2-transgenic mice but exaggerated in hepatic Tipe2-knockout mice treated by metabolic challenges. RNA sequencing revealed that TIPE2 was significantly associated with the mitogen-activated protein kinase pathway. Mechanistic experiments demonstrated that TIPE2 bound with transforming growth factor beta–activated kinase 1 (TAK1), prevented tumor necrosis factor receptor–associated factor 6–mediated TAK1 ubiquitination and subsequently inhibited the TAK1 phosphorylation and activation of TAK1–c-Jun N-terminal kinase (JNK)/p38 signaling. Further investigation showed that blocking the activity of TAK1 reversed the worsening of hepatic metabolic disorders and inflammation in hepatic-specific Tipe2-knockout hepatocytes and mice treated with metabolic stimulation.
Conclusions
TIPE2 suppresses NAFLD advancement by blocking TAK1-JNK/p38 pathway and is a promising target molecule for NAFLD therapy.
Supporting Information
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| hep31832-sup-0001-Supinfo.docxWord document, 10.8 MB | Supplementary Material |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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Author names in bold designate shared co-first authorship.
