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Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression.

Publication ,  Journal Article
Bai, L; Qu, W; Cheng, X; Yang, H; Huang, Y-P; Wang, Z; Han, C; Tian, R-F; Hu, F; Yang, L; Tian, S; Tian, H; Cai, Z; Wan, J; Jiang, J ...
Published in: Sci Transl Med
February 14, 2024

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-β-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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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

February 14, 2024

Volume

16

Issue

734

Start / End Page

eade7347

Location

United States

Related Subject Headings

  • Signal Transduction
  • Non-alcoholic Fatty Liver Disease
  • Mitogen-Activated Protein Kinases
  • Mice
  • Liver
  • Intracellular Signaling Peptides and Proteins
  • Hepatocytes
  • Gene Expression Profiling
  • Animals
  • 4003 Biomedical engineering
 

Citation

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Bai, L., Qu, W., Cheng, X., Yang, H., Huang, Y.-P., Wang, Z., … Zhang, X.-J. (2024). Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression. Sci Transl Med, 16(734), eade7347. https://doi.org/10.1126/scitranslmed.ade7347
Bai, Lan, Weiyi Qu, Xu Cheng, Hailong Yang, Yong-Ping Huang, Zhenya Wang, Cuijuan Han, et al. “Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression.Sci Transl Med 16, no. 734 (February 14, 2024): eade7347. https://doi.org/10.1126/scitranslmed.ade7347.
Bai L, Qu W, Cheng X, Yang H, Huang Y-P, Wang Z, et al. Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression. Sci Transl Med. 2024 Feb 14;16(734):eade7347.
Bai, Lan, et al. “Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression.Sci Transl Med, vol. 16, no. 734, Feb. 2024, p. eade7347. Pubmed, doi:10.1126/scitranslmed.ade7347.
Bai L, Qu W, Cheng X, Yang H, Huang Y-P, Wang Z, Han C, Tian R-F, Hu F, Yang L, Tian S, Tian H, Cai Z, Wan J, Jiang J, Fu J, Zhou J, Hu Y, Ma T, Zhang X, Ji Y-X, Cai J, She Z-G, Wang Y, Zhang P, Huang L, Li H, Zhang X-J. Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression. Sci Transl Med. 2024 Feb 14;16(734):eade7347.

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

February 14, 2024

Volume

16

Issue

734

Start / End Page

eade7347

Location

United States

Related Subject Headings

  • Signal Transduction
  • Non-alcoholic Fatty Liver Disease
  • Mitogen-Activated Protein Kinases
  • Mice
  • Liver
  • Intracellular Signaling Peptides and Proteins
  • Hepatocytes
  • Gene Expression Profiling
  • Animals
  • 4003 Biomedical engineering