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

Abstract

The 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. Five hundred and eightyeight 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 (OGT) overexpression and O-GlcNAcase inhibition by genetic or pharmaceutical manipulations increased AIMP2 and PARP1 levels in vitro. Mechanistically, O-GlcNAcylation increased AIMP2 protein stability, leading to its aggregation. Our study reveals O-GlcNAcylated AIMP2 as a novel pathogenic regulator of aging-related hepatic steatosis.

Biological Functions and Potential Therapeutic Significance of O-GlcNAcylation in Hepatic Cellular Stress and Liver Diseases

“…Reduced nutrient-sensing activity and metabolic disorder are the main features of aging and NAFLD [99,100]. A recent study has revealed that aging-related fatty liver induced by the dysregulation of O-GlcNAcylation is closely associated with aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) and poly (ADP-ribose, PAR) polymerase 1 (PARP1) [101]. AIMP2 can induce an increase in PARP1 hyperactivation in the liver of aged mice, possibly via a direct protein-protein association, leading to PAR accumulation.…”

“…AIMP2 can induce an increase in PARP1 hyperactivation in the liver of aged mice, possibly via a direct protein-protein association, leading to PAR accumulation. O-GlcNAc signaling has also been found to be significantly activated in aging-related fatty liver to reduce AIMP2 degradation [101]. Considering that PARP1 is the most abundant of the PARP family of enzymes in response to DNA damage during aging [102], it has been speculated that an overactivated AIMP2-PARP1 axis may partially contribute to NAD + depletion [101].…”

“…O-GlcNAc signaling has also been found to be significantly activated in aging-related fatty liver to reduce AIMP2 degradation [101]. Considering that PARP1 is the most abundant of the PARP family of enzymes in response to DNA damage during aging [102], it has been speculated that an overactivated AIMP2-PARP1 axis may partially contribute to NAD + depletion [101]. Higher NAD + levels can enhance the activity of sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which have been reported to protect mice from fatty liver diseases such as NAFLD [103,104].…”

Protein O‐GlcNAcylation: The sweet hub in liver metabolic flexibility from a (patho)physiological perspective

“…O ‐GlcNAcylation is considered a potential therapeutic target, and blocking O ‐GlcNAcylation of nuclear factor kappa‐B (NF‐κB) p65 ameliorates inflammation in a NASH mouse model 162–164 . Meanwhile, O ‐GlcNAcylation of aminoacyl tRNA synthetase complex‐interacting multifunctional protein 2 increases its stability and aggregation, leading to promotion of poly(adenosine diphosphate ribose) polymerase 1 activation in ageing‐related hepatic steatosis 165 . O ‐GlcNAcylation of sterile alpha motif and histidine/aspartic acid domain‐containing protein 1 at Ser 93 enhances its stability and antiviral activity, thereby positively regulating the host's natural antiviral response against hepatitis B virus 166 .…”

“…[162][163][164] Meanwhile, O-GlcNAcylation of aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 increases its stability and aggregation, leading to promotion of poly(adenosine diphosphate ribose) polymerase 1 activation in ageing-related hepatic steatosis. 165 O-GlcNAcylation of sterile alpha motif and histidine/ aspartic acid domain-containing protein 1 at Ser 93 enhances its stability and antiviral activity, thereby positively regulating the host's natural antiviral response against hepatitis B virus. 166 Some similar positive effects were observed for hepatitis C virus, including preventing their ability to induce hepatopathy and hepatocellular carcinoma.…”