Ubiquitin-specific protease 4 is an endogenous negative regulator of metabolic dysfunctions in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, insulin resistance and inflammation, poses a high risk of cardiometabolic disorders. Ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme, is pivotally involved in regulating multiple inflammatory pathways; however, the role of USP4 in NAFLD is unknown. Here we report that USP4 expression was dramatically downregulated in the livers from NAFLD patients and different NAFLD mouse models induced by a high fat diet (HFD) or a genetic deficiency (ob/ob) as well as in palmitate-treated hepatocytes. Hepatocyte-specific USP4 depletion exacerbated hepatic steatosis, insulin resistance and inflammatory response in HFD-induced NAFLD mice. Conversely, hepatic USP4 overexpression notably alleviated the pathological alterations in two different NAFLD models. Mechanistically, hepatocyte USP4 directly bound to and deubiquitinated transforming growth factor-β activated kinase 1 (TAK1), leading to a suppression of the activation of downstream NF-κB and JNK cascades, which in turn reversed the disruption of the IRS-AKT-GSK3β signaling. In addition, USP4-TAK1 interaction and subsequent TAK1 deubiquitination were required for the amelioration of metabolic dysfunctions. Collectively, the present study provides the first evidence that USP4 functions as a pivotal suppressor in NAFLD and related metabolic disorders. This article is protected by copyright. All rights reserved.