LAUSR

BACKGROUND AND AIMS As a global health threat, nonalcoholic steatohepatitis (NASH) has been confirmed to be a chronic progressive liver disease that is strongly associated with obesity. However, no approved drugs or efficient therapeutic strategies are valid, practically because its complicated pathologic processes is underestimated. APPROACH AND RESULTS We identified the RING-type E3 ubiquitin transferase-tripartite motif-containing protein 31 (TRIM31), a member of E3 ubiquitin ligases family, as a novel and efficient endogenous inhibitor of transforming growth factor-beta-activated kinase 1 (MAP3K7), and we further confirmed that TRIM31 is an MAP3K7-interacting protein and promotes MAP3K7 degradation by enhancing ubiquitination of K48-linkage in hepatocytes. Hepatocyte-specific Trim31 deletion blocks hepatic metabolism homeostasis, concomitant with glucose metabolic syndrome, lipid accumulation, upregulated inflammation, and dramatically facilitates NASH progression. Inversely, transgenic overexpression, lentivirus or adeno-associated virus-mediated Trim31 gene therapy restrains NASH in three dietary mice models. Mechanistically, in response to metabolic insults, TRIM31 interacts with MAP3K7, and conjugates K48-linked ubiquitination chains to promotes MAP3K7 degradation, thus blocks MAP3K7 abundance and its downstream signaling cascade activation in hepatocytes. CONCLUSIONS TRIM31 may serve as a promising therapeutic target for NASH treatment and associated metabolic disorders.