Emerging Role of Protein O-GlcNAcylation in Liver Metabolism: Implications for Diabetes and NAFLD

Abstract

O-linked b-N-acetyl-glucosaminylation (O-GlcNAcylation) is one of the most common post-translational modifications of proteins, and is established by modifying the serine or threonine residues of nuclear, cytoplasmic, and mitochondrial proteins. O-GlcNAc signaling is considered a critical nutrient sensor, and affects numerous proteins involved in cellular metabolic processes. O-GlcNAcylation modulates protein functions in different patterns, including protein stabilization, enzymatic activity, transcriptional activity, and protein interactions. Disrupted O-GlcNAcylation is associated with an abnormal metabolic state, and may result in metabolic disorders. As the liver is the center of nutrient metabolism, this review provides a brief description of the features of the O-GlcNAc signaling pathway, and summarizes the regulatory functions and underlying molecular mechanisms of O-GlcNAcylation in liver metabolism. Finally, this review highlights the role of O-GlcNAcylation in liver-associated diseases, such as diabetes and nonalcoholic fatty liver disease (NAFLD). We hope this review not only benefits the understanding of O-GlcNAc biology, but also provides new insights for treatments against liver-associated metabolic disorders.

FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid

“…FXR activation enhances glycogen synthesis by promoting direct or indirect phosphorylation of glycogen synthase kinase‐3 beta, a pivotal modulator in glycogen synthase pathway 27 . It also governs gluconeogenesis via phosphoenolpyruvate carboxykinase and glucose‐6‐phosphatase 13 as well as inhibits glycolysis via carbohydrate response element‐binding protein 28 and glucagon‐like peptide 1 (GLP‐1) 29 . Additionally, FXR activation promotes β‐oxidation of fatty acids and regulate serum lipoprotein levels via peroxisome proliferator‐activated receptor alpha, 30 sterol regulatory element‐binding protein‐1c, 31 apolipoprotein A‐I, 32 apolipoprotein B, 33 and apolipoprotein C‐II/III, 32 resulting in a reduction in hepatic fat content.…”

O-GlcNAcylation of YTHDF2 antagonizes ERK-dependent phosphorylation and inhibits lung carcinoma

“…It is catalyzed by the O-GlcNAc transferase (OGT) and removed by the O-GlcNAcase (OGA). Decades of glycobiology research have witnessed emerging chemical and biological tools (3,4) that have demonstrated that O-GlcNAc occurs on about 5 000 proteins and regulates tumorigenesis and immunotherapy (5), ferroptosis (6), protein aggregation and phase separation (7), stem cell biology (8), liver metabolism (9), neurodevelopment and various stress response pathways (10).…”