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Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression.
Bai, Lan; Qu, Weiyi; Cheng, Xu; Yang, Hailong; Huang, Yong-Ping; Wang, Zhenya; Han, Cuijuan; Tian, Rui-Feng; Hu, Fengjiao; Yang, Ling; Tian, Song; Tian, Han; Cai, Zhiwei; Wan, Juan; Jiang, Jingwei; Fu, Jiajun; Zhou, Junjie; Hu, Yufeng; Ma, Tengfei; Zhang, Xin; Ji, Yan-Xiao; Cai, Jingjing; She, Zhi-Gang; Wang, Yibin; Zhang, Peng; Huang, Lingli; Li, Hongliang; Zhang, Xiao-Jing.
Afiliación
  • Bai L; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China.
  • Qu W; State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Ganzhou 341008, China.
  • Cheng X; Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan 430060, China.
  • Yang H; Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan 430060, China.
  • Huang YP; Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430060, China.
  • Wang Z; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China.
  • Han C; State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Ganzhou 341008, China.
  • Tian RF; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China.
  • Hu F; State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Ganzhou 341008, China.
  • Yang L; College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • Tian S; Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan 430060, China.
  • Tian H; School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
  • Cai Z; Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan 430060, China.
  • Wan J; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
  • Jiang J; Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan 430060, China.
  • Fu J; School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
  • Zhou J; Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan 430060, China.
  • Hu Y; Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan 430060, China.
  • Ma T; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China.
  • Zhang X; State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Ganzhou 341008, China.
  • Ji YX; Jiangsu Key Lab of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
  • Cai J; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China.
  • She ZG; State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Ganzhou 341008, China.
  • Wang Y; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China.
  • Zhang P; State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Ganzhou 341008, China.
  • Huang L; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China.
  • Li H; State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Ganzhou 341008, China.
  • Zhang XJ; Department of Neurology, Huanggang Central Hospital, Huanggang 438000, China.
Sci Transl Med ; 16(734): eade7347, 2024 Feb 14.
Article en En | MEDLINE | ID: mdl-38354227
ABSTRACT
Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across multiple species. Furthermore, we identified suppressor of IKKε (SIKE) as a conserved and potent negative controller of MAPK activation. Hepatocyte-specific overexpression of Sike prevented NASH progression in diet- and toxin-induced mouse NASH models. Mechanistically, SIKE directly interacted with TGF-ß-activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) to interrupt their binding and subsequent TAK1-MAPK signaling activation. We found that indobufen markedly up-regulated SIKE expression and effectively improved NASH features in mice and macaques. These findings identify SIKE as a MAPK suppressor that prevents NASH progression and provide proof-of-concept evidence for targeting the SIKE-TAK1 axis as a potential NASH therapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad del Hígado Graso no Alcohólico Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad del Hígado Graso no Alcohólico Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos