A nexus of lipid and O-Glcnac metabolism in physiology and disease

Abstract

Although traditionally considered a glucose metabolism-associated modification, the O-linked β-N-Acetylglucosamine (O-GlcNAc) regulatory system interacts extensively with lipids and is required to maintain lipid homeostasis. The enzymes of O-GlcNAc cycling have molecular properties consistent with those expected of broad-spectrum environmental sensors. By direct protein-protein interactions and catalytic modification, O-GlcNAc cycling enzymes may provide both acute and long-term adaptation to stress and other environmental stimuli such as nutrient availability. Depending on the cell type, hyperlipidemia potentiates or depresses O-GlcNAc levels, sometimes biphasically, through a diversity of unique mechanisms that target UDP-GlcNAc synthesis and the availability, activity and substrate selectivity of the glycosylation enzymes, O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA). At the same time, OGT activity in multiple tissues has been implicated in the homeostatic regulation of systemic lipid uptake, storage and release. Hyperlipidemic patterns of O-GlcNAcylation in these cells are consistent with both transient physiological adaptation and feedback uninhibited obesogenic and metabolic dysregulation. In this review, we summarize the numerous interconnections between lipid and O-GlcNAc metabolism. These links provide insights into how the O-GlcNAc regulatory system may contribute to lipid-associated diseases including obesity and metabolic syndrome.

Combining Selective Enrichment and a Boosting Approach to Globally and Site-Specifically Characterize Protein Co-translational O-GlcNAcylation

“…It is well-known that O -GlcNAc is a prominent component of the stress granule, and during heat stress, O -GlcNAcylation of eIF4G is critical for the translation of mRNAs for proteins responding to the stress. , O -GlcNAcylation also plays a multifaceted role in the cell cycle, and it regulates gene expression by modifying a large subset of transcription-related proteins and modulates the functions of proteins involved in the spindle apparatus and cytokinesis . Furthermore, O -GlcNAcylation serves as a nutrient sensor that is not only related to glucose metabolism but also involved in the metabolism of other nutrients, including lipids . Six proteins identified with co-translational O -GlcNAcylation are associated with lipid metabolism.…”

“…64 Furthermore, O-GlcNAcylation serves as a nutrient sensor that is not only related to glucose metabolism but also involved in the metabolism of other nutrients, including lipids. 65 Six proteins identified with co-translational O-GlcNAcylation are associated with lipid metabolism. Additionally, O-GlcNAcylation regulates multiple signaling pathways, making it an excellent signal integrator for a wide range of cellular events.…”

Control of lipid metabolism by the dynamic and nutrient‐dependent post‐translational modification O‐GlcNAcylation

“…It has been shown in various tissues (human stomach, liver and skeletal muscle; mouse intestine and adipose; rat skeletal muscle and heart) that hyperlipidemia interferes with the O-GlcNAcylation content as extensively discussed in a recent paper 45 (Figure 3). Obesity and highfat diet increase O-GlcNAcylation in numerous mice tissues with the exception of hippocampus, pancreatic islets, and macrophages.…”

“…Obesity and high‐fat diet increase O ‐GlcNAcylation in numerous mice tissues with the exception of hippocampus, pancreatic islets, and macrophages. Also, long‐chain fatty acids enhance the level of O ‐GlcNAcylation in various ex vivo models (e.g., rat L6 myotubes, immortalized cell lines, human gastric‐derived cell lines) but decrease it in the human neuroblastoma cell line SH‐SY5Y 45 (Figure 3).…”

Fetal Reprogramming of Nutrient Surplus Signaling, O-GlcNAcylation, and the Evolution of CKD

“…The subsequent addition of uridine triphosphate (with the release of one phosphate) yields UDP-GlcNAc, the end product of the hexosamine biosynthetic pathway. 90 It is noteworthy that the structural constituents of UDP-GlcNAc reflect all key elements of cellular metabolism, including those involving glucose and amino acids (glucosamine), glucose and fatty acids (acetyl) highenergy metabolism (diphosphate), and nucleoside synthesis (uridine), and thus, UDP-GlcNAc dynamically integrates multiple energy signals, [91][92][93] allowing it to be well-positioned as a nutrient surplus sensor.…”