TY - JOUR TI - Tumor necrosis factor-α-induced protein 8-like 2 alleviates nonalcoholic fatty liver disease via suppressing TAK1 activation AU - Liu, Yupeng AU - Song, Jingjing AU - Yang, Juan AU - Zheng, Jilin AU - Yang, Ling AU - Gao, Jun AU - Tian, Song AU - Liu, Zhen AU - Meng, Xiangbin AU - Wang, Jian-Cheng AU - Dai, Zhifei AU - Tang, Yi-Da T2 - Hepatology AB - Background & Aims Worldwide, Nonalcoholic fatty liver disease (NAFLD) prevalence increases rapidly and becomes 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. But the function of TIPE2 in NAFLD remained unknown. Here, we investigated the role of TIPE2 in the development of NAFLD. Approach & Results Our study found 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 TIPE2 was significantly associated with the mitogen-activated protein kinase (MAPK) pathway. Mechanistic experiments demonstrated that TIPE2 bound with transforming growth factor-beta-activated kinase 1 (TAK1) under metabolic stress, prevented tumor necrosis factor receptor-associated factor 6 (TRAF6)-mediated TAK1 ubiquitination and subsequently inhibited the phosphorylation and activation of TAK1-c-Jun NH2-terminal kinase (JNK)/p38 signaling. Further investigation showed that blocking the activity of TAK1 reversed the worsening of hepatic metabolic disorders and inflammation in TIPE2-HKO 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. DO - https://doi.org/10.1002/hep.31832 DP - Wiley Online Library VL - n/a IS - n/a LA - en SN - 1527-3350 UR - https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.31832 Y2 - 2021/03/26/20:33:26 KW - MAPK KW - Metabolic diorders KW - NAFLD KW - TAK1 KW - TIPE2 ER -