TIPE1 Inhibits Hepatic Steatosis, Inflammation, and Fibrosis by Suppressing Polyubiquitination of ASK1.

Characterized by hepatocyte steatosis, inflammation, and fibrosis, nonalcoholic steatohepatitis (NASH) is a complicated process that contributes to end-stage liver disease and, eventually, hepatocellular carcinoma (HCC). Tumor necrosis factor alpha (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. Here, we revealed 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 challenges, thereby inhibiting downstream c-Jun N-terminal kinase (JNK) and p38 signaling pathway. Importantly, dramatically reduced TIPE1 expression was observed in the livers of nonalcoholic fatty liver disease (NAFLD) patients, suggesting that TIPE1 might be a promising therapeutic target for NAFLD and related metabolic diseases. Conclusion: 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.