Abstract | BACKGROUND AND AIMS: 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.
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Authors | Yupeng Liu, Jingjing Song, Juan Yang, Jilin Zheng, Ling Yang, Jun Gao, Song Tian, Zhen Liu, Xiangbin Meng, Jian-Cheng Wang, Zhifei Dai, Yi-Da Tang |
Journal | Hepatology (Baltimore, Md.)
(Hepatology)
Vol. 74
Issue 3
Pg. 1300-1318
(09 2021)
ISSN: 1527-3350 [Electronic] United States |
PMID | 33768585
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2021 by the American Association for the Study of Liver Diseases. |
Chemical References |
- Intracellular Signaling Peptides and Proteins
- TIPE2 protein, mouse
- MAP Kinase Kinase Kinases
- MAP kinase kinase kinase 7
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Topics |
- Animals
- Diet, High-Fat
- Hepatocytes
(metabolism, pathology)
- Inflammation
- Insulin Resistance
(genetics)
- Intracellular Signaling Peptides and Proteins
(genetics, metabolism)
- Liver Cirrhosis
(genetics, metabolism, pathology)
- MAP Kinase Kinase Kinases
(metabolism)
- MAP Kinase Signaling System
(genetics)
- Mice
- Mice, Knockout
- Mice, Transgenic
- Non-alcoholic Fatty Liver Disease
(genetics, metabolism, pathology)
- Ubiquitination
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