OGT-mediated AIMP2 O-GlcNAcylation promotes PARP1 overactivation in ageing-associated liver steatosis

The incidence of non-alcoholic fatty liver disease (NAFLD) increases with ageing. However, the molecular mechanism of ageing-related NAFLD is far from clear. Recent advances in mass spectrometry allowed us to identify amounts of proteins and find new mechanisms. Here, we examined hepatic lipid, metabolic cage study and gut microbiota composition in young and old mice. Using proteomics analysis, 588 differential proteins were identified and some of them are involved in cellular processes widely recognized as hallmarks for aging, such as changed methylation, loss of proteostasis (protein folding alteration, decreased autophagy, and increased ubiquitination) ,increased apoptosis, dysregulated rhythmic process, and bile acid metabolism. We also demonstrated the levels of AIMP2 and O-GlcNAc transferase (OGT) were dramatically upregulated in the livers of old mice. AIMP2 accumulation led to PARP1 overactivation, causing liver NAD+ deletion. Moreover, overexpression OGT and O-GlcNAcaseinhibition by genetic or pharmaceutical manipulations increased AIMP2 and PARP1 expression in hepatic cells. Mechanistically, OGT-mediated AIMP2 O-GlcNAcylation promoted AIMP2 aggregation. Together, our work greatly expanded the potential aging-associated protein markers. Targeted inhibition of the AIMP2-PARP1 pathway might be useful as a therapeutic approach for ageing-related NAFLD.