Comparative proteomic profiling reveals a pathogenic role for the O ‐GlcNAcylated AIMP2–PARP1 complex in aging‐related hepatic steatosis in mice

In a mouse model of aging-related hepatic steatosis, 588 aging-related differentially expressed proteins (DEPs) were identified in the livers of old mice using liquid chromatography –mass spectrometry. Among them, AIMP2 was the most significantly upregulated protein. Aging induced the activation of O-GlcNAcylation and increased AIMP2 O-GlcNAcylation. The AIMP2 O-GlcNAcylation promoted PARP1 overactivation, thereby causing liver NAD+ deletion and hepatic steatosis. AbstractThe prevalence of non-alcoholic fatty liver disease (NAFLD) increases with aging. However, the mechanism of aging-related NAFLD remains unclear. Herein, we constructed an aging-related hepatic steatosis model and analyzed the differentially expressed proteins (DEPs) in livers from young and old mice using liquid chromatography –mass spectrometry. 588 aging-related DEPs and novel pathways were identified. Aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2), the most significantly upregulated protein, promoted poly(ADP-ribose) polymerase 1 (PARP1) activation in aging-related hepatic steatosis. Additionally, mice liver-specific O-GlcNAcase knockout promoted AIMP2 and PARP1 expression. O-GlcNAc transferase overexpression and O-GlcNAcase inhibition by genetic or pharmaceutical manipulations increased AIMP2 and PARP1 levelsin vitro. Mechanistically, O-GlcNAcylation increased AIMP2 protein stability, leading to its aggregation. Our study reveals O-GlcNAcylated AIMP2 as a novel pathog...
Source: FEBS Letters - Category: Biochemistry Authors: Tags: Research Article Source Type: research