O-GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis

Ortega-Prieto, Paula; Parlati, Lucia; Benhamed, Fadila; Régnier, Marion; Cavalcante, Isadora Pontes; Montabord, Mélanie; Onifarasoaniaina, Rachel; Favier, Maryline; Pavlović, Nataša; Magusto, Julie; Caüzac, Michèle; Pagésy, Patrick; Gautheron, Jérémie; Guilmeau, Sandra; Issad, Tarik; Postic, Catherine

doi:10.1016/j.jhepr.2023.100878

Cited by 3 publications

(2 citation statements)

References 41 publications

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“…168 Recently, another group also reported that OGT deficiency is associated with hepatic oxidative stress, DNA damage, together with liver inflammation and advanced fibrosis. 169 Fibrosis progression is driven by repeated repair periods with excessive deposition of extracellular matrix. 170 Activated hepatic stellate cells (HSCs) are the main source of extracellular matrix in liver, and O-GlcNAcylation is essential for regulating HSC activation.…”

Section: Abnormalo-glcnacylationnashand Hepatic Fibrosismentioning

confidence: 99%

“…NAFLD progresses to NASH, and NASH often leads to hepatic fibrosis and ultimately cirrhosis 168 . Recently, another group also reported that OGT deficiency is associated with hepatic oxidative stress, DNA damage, together with liver inflammation and advanced fibrosis 169 . Fibrosis progression is driven by repeated repair periods with excessive deposition of extracellular matrix 170 .…”

Section: Abnormal O‐glcnacylation Is Associated With the Aetiology Of...mentioning

confidence: 99%

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

Hu,

Zhang,

et al. 2023

Liver International

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O‐GlcNAcylation is a dynamic, reversible and atypical O‐glycosylation that regulates various cellular physiological processes via conformation, stabilisation, localisation, chaperone interaction or activity of target proteins. The O‐GlcNAcylation cycle is precisely controlled by collaboration between O‐GlcNAc transferase and O‐GlcNAcase. Uridine‐diphosphate‐N‐acetylglucosamine, the sole donor of O‐GlcNAcylation produced by the hexosamine biosynthesis pathway, is controlled by the input of glucose, glutamine, acetyl coenzyme A and uridine triphosphate, making it a sensor of the fluctuation of molecules, making O‐GlcNAcylation a pivotal nutrient sensor for the metabolism of carbohydrates, amino acids, lipids and nucleotides. O‐GlcNAcylation, particularly prevalent in liver, is the core hub for controlling systemic glucose homeostasis due to its nutritional sensitivity and precise spatiotemporal regulation of insulin signal transduction. The pathology of various liver diseases has highlighted hepatic metabolic disorder and dysfunction, and abnormal O‐GlcNAcylation also plays a specific pathological role in these processes. Therefore, this review describes the unique features of O‐GlcNAcylation and its dynamic homeostasis maintenance. Additionally, it explains the underlying nutritional sensitivity of O‐GlcNAcylation and discusses its mechanism of spatiotemporal modulation of insulin signal transduction and liver metabolic homeostasis during the fasting and feeding cycle. This review emphasises the pathophysiological implications of O‐GlcNAcylation in nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and hepatic fibrosis, and focuses on the adverse effects of hyper O‐GlcNAcylation on liver cancer progression and metabolic reprogramming.

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Section: Abnormalo-glcnacylationnashand Hepatic Fibrosismentioning

confidence: 99%

Section: Abnormal O‐glcnacylation Is Associated With the Aetiology Of...mentioning

confidence: 99%

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

Hu,

Zhang,

et al. 2023

Liver International

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O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in myofibroblasts

Very,

Boulet,

Gheeraert

et al. 2024

Cell Death Dis

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Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O-linked β-D-N-acetylglucosaminylation (O-GlcNAcylation) is increased and required for myofibroblastic activation. Inhibition of protein O-GlcNAcylation impairs archetypal myofibloblast cellular activities including extracellular matrix gene expression and collagen secretion/deposition as defined in vitro and using ex vivo and in vivo murine liver injury models. Mechanistically, a multi-omics approach combining proteomic, epigenomic, and transcriptomic data mining revealed that O-GlcNAcylation controls the MF transcriptional program by targeting the transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes-associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O-GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of the MF transcriptional regulatory landscape. We found that this involves O-GlcNAcylation of BNC2 at Thr455 and Ser490 and of TEAD4 at Ser69 and Ser99. Altogether, this study unravels protein O-GlcNAcylation as a key determinant of myofibroblastic activation and identifies its inhibition as an avenue to intervene with fibrogenic processes.

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La O-GlcNAc transférase

Parlati,

Regnier,

Benhamed

et al. 2024

Med Sci (Paris)

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O-GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis

Cited by 3 publications

References 41 publications

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

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

O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in myofibroblasts

La O-GlcNAc transférase

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