OTUB1 mediates PARP1 deubiquitination to alleviate NAFLD by regulating HMGB1

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease characterized by hepatocyte steatosis, which excludes alcohol, drugs and other definite liver damage-related factors. It has been reported that OTUB1 serves a significant role in the regulation of glucose and lipid metabolism. The present study aimed to investigate the molecular mechanism underlying the effect of OTUB1 on regulating NAFLD. The NAFLD mouse model was induced via high-fat-diet, and glucose and insulin tolerance tests were then performed. In addition, the serum levels of total cholesterol (TC) and triglycerides (TG) were detected. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were assessed using the corresponding biochemical assays. Hematoxylin and eosin, and periodic acid-Schiff staining was carried out to evaluate the liver pathology in mice. The expression levels of the NAFLD-related genes and inflammatory genes were determined by reverse transcription-quantitative PCR, Western blot analysis and immunofluorescence staining. Furthermore, the regulatory association between OTUB1 and poly (adenosine diphosphate-ribose) polymerase (PARP)-1 was assessed by co-immunoprecipitation assay. The results showed that OTUB1 was significantly upregulated in both in vitro and in vivo NAFLD models. Knockout of OTUB1 significantly improved affected glucose tolerance and insulin sensitivity, decreased TG and TC content, and decreased ALT, AST and ALP levels. In addition, the results show that OTUB1 can regulate the expression of PARP1 by inhibiting the ubiquitination of PARP1, while PARP1 knockout can inhibit liver inflammation by regulating HMGB1, thereby improving NAFLD. Targeting OTUB1 could be a potential therapeutic strategy for the NAFLD.