Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression.
Lan BaiWeiyi QuXu ChengHailong YangYong-Ping HuangZhenya WangCuijuan HanRui-Feng TianFengjiao HuLing YangSong TianHan TianZhiwei CaiJuan WanJingwei JiangJiajun FuJunjie ZhouYufeng HuTeng-Fei MaXin ZhangYan-Xiao JiJingjing CaiZhi-Gang SheYibin WangPeng ZhangLingli HuangHong Liang LiXiao-Jing ZhangPublished in: Science translational medicine (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.
Keyphrases
- signaling pathway
- oxidative stress
- binding protein
- pi k akt
- transcription factor
- physical activity
- escherichia coli
- type diabetes
- stem cells
- poor prognosis
- adipose tissue
- gene expression
- epithelial mesenchymal transition
- genome wide
- bone marrow
- transforming growth factor
- cancer therapy
- mouse model
- insulin resistance
- cell therapy
- high glucose
- human health