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

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.