Abstract

Background Metabolic-associated fatty liver disease (MAFLD) is a common chronic liver disease caused by lipid accumulation in hepatocytes, and multiple deubiquitinating enzymes (DUBs) have been reported to play roles in the pathogenesis of MAFLD. However, the role of ubiquitin-specific protease 47 (USP47) in MAFLD remains unclear. Methods MAFLD models were established in rats by a high-fat diet (HFD) and in HepG2 cells by oleic acid (OA) induction. The expression of related genes and proteins was detected via RT–qPCR, Western blotting, immunofluorescence, and immunohistochemistry. Cell damage was assessed through CCK-8 assays, flow cytometry, Oil Red O staining, and glucose uptake assays. Results USP47 was expressed at low levels in MAFLD models. In MAFLD model rats, Usp47 overexpression reduced body weight, fasting blood glucose, insulin levels, and insulin resistance; decreased serum TC, TG, and FFA levels; and ameliorated liver dysfunction and liver tissue pathological damage. Additionally, in the OA-induced HepG2 MAFLD model, USP47 overexpression increased cell viability; decreased apoptosis, lipid accumulation, TC, TG, and FFA levels; and increased glucose uptake capacity. Mechanistically, USP47 stabilized SIRT1 expression through deubiquitination, and SIRT1 upregulated PPARα expression via deacetylation. The SIRT1 inhibitor EX-527 and the PPARα inhibitor TPST-1120 weakened the alleviating effects of USP47 overexpression on OA-induced cellular damage and MAFLD in rats. The effect of USP47 knockdown was opposite to that of USP47 overexpression. Conclusion USP47 inhibits the ubiquitination and degradation of SIRT1 and stabilizes its expression. SIRT1, in turn, increases PPARα expression through deacetylation, thereby promoting lipid metabolism and alleviating MAFLD.