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.