Ubiquitin-specific peptidase 10 ameliorates hepatic steatosis in nonalcoholic steatohepatitis model by restoring autophagic activity.

ABSTRACT

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a critical event in the progression of nonalcoholic fatty liver disease (NAFLD). Steatosis induces lipotoxicity, driving the transition of simple fatty liver (NAFL) to NASH. Autophagy affects NAFLD by improving steatosis. AIM: To investigate whether ubiquitin-specific peptidase (USP)10 alleviates hepatic steatosis through autophagy. METHODS: A methionine-choline-deficient diet (MCDD) and choline-deficient diet (CDD) were used to model rodent NASH and NAFL, respectively. HepG2 cells were treated with palmitic acid to model hepatocellular steatosis. A viral carrier was used to regulate the USP10 level. Real-time fluorescence quantitative polymerase chain reaction, western blotting, histology, and electron microscopy were used to detect autophagic activity and steatosis. RESULTS: In vivo, a time-dependent correlation of USP10 and autophagic activity in the liver was found during NAFLD (including NAFL and NASH) modeling. After 8 weeks of modeling, the autophagic activity of NASH was lower than that of the healthy controls and those with NAFL. USP10 could promote autophagy-related pathways and molecules and increase the synthesis of autophagosomes in NASH, improving steatosis, inflammation, and fibrosis. In vitro, autophagy inhibitors reversed the lipid-lowering effect of USP10 without decreasing the level of fatty acid ß-oxidation. CONCLUSION: USP10 ameliorated histological steatosis, inflammation, and fibrosis. USP10 alleviated hepatic steatosis in NASH in an autophagy-dependent manner.