TNF-α-Induce Protein 8-Like 1 Inhibits Hepatic Steatosis, Inflammation, and Fibrosis by Suppressing Polyubiquitination of Apoptosis Signal-Regulating Kinase 1.

Abstract

BACKGROUND AND AIMS:

Characterized by hepatocyte steatosis, inflammation, and fibrosis, NASH is a complicated process that contributes to end-stage liver disease and, eventually, HCC. TNF-α-induced protein 8-like 1 (TIPE1), a new member of the TNF-α-induced protein 8 family, has been explored in immunology and oncology research; but little is known about its role in metabolic diseases.

APPROACH AND RESULTS:

Here, we show that hepatocyte-specific deletion of TIPE1 exacerbated diet-induced hepatic steatosis, inflammation, and fibrosis as well as systemic metabolic disorders during NASH pathogenesis. Conversely, hepatocyte-specific overexpression of TIPE1 dramatically prevented the progression of these abnormalities. Mechanically, TIPE1 directly interacted with apoptosis signal-regulating kinase 1 (ASK1) to suppress its TNF receptor-associated factor 6 (TRAF6)-catalyzed polyubiquitination activation upon metabolic challenge, thereby inhibiting the downstream c-Jun N-terminal kinase and p38 signaling pathway. Importantly, dramatically reduced TIPE1 expression was observed in the livers of patients with NAFLD, suggesting that TIPE1 might be a promising therapeutic target for NAFLD and related metabolic diseases.

CONCLUSIONS:

TIPE1 protects against hepatic steatosis, inflammation, and fibrosis through directly binding ASK1 and restraining its TRAF6-catalyzed polyubiquitination during the development of NASH. Therefore, targeting TIPE1 could be a promising therapeutic approach for NAFLD treatment.

• Authors: Hong Wu, Xiaolei Xu, Ancheng Zheng, Weina Wang, Li Mei, Yue Chen, Shasha Sun, Liujun Jiang, Yutao Wu, Yijiang Zhou, Min Zheng, Qishan Chen
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 74 Issue 3 Pg. 1251-1270 (09 2021) ISSN: 1527-3350 [Electronic] United States
• PMID: 33713358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by the American Association for the Study of Liver Diseases.

Chemical References

• Intracellular Signaling Peptides and Proteins
• TIPE1 protein, mouse
• TNFAIP8L1 protein, human
• Polyubiquitin
• MAP Kinase Kinase Kinase 5

Topics

• Adult
• Aged
• Animals
• Diet, High-Fat
• Down-Regulation
• Fatty Liver (genetics, metabolism, pathology)
• Female
• Humans
• Inflammation
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Liver Cirrhosis (genetics, metabolism, pathology)
• MAP Kinase Kinase Kinase 5 (metabolism)
• Male
• Mice, Knockout
• Mice, Transgenic
• Middle Aged
• Non-alcoholic Fatty Liver Disease (genetics, metabolism)
• Polyubiquitin (metabolism)