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

Autor:	Ortega-Prieto P; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France., Parlati L; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France., Benhamed F; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France., Regnier M; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France., Cavalcante I; Team Genomics and Signaling of Endocrine Tumors, Institut Cochin, CNRS, INSERM, Université Paris Cité, Paris, France., Montabord M; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France., Onifarasoaniaina R; HistIM Platform, Institut Cochin, CNRS, INSERM, Université de Paris Cité, Paris, France., Favier M; HistIM Platform, Institut Cochin, CNRS, INSERM, Université de Paris Cité, Paris, France., Pavlovic N; Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France., Magusto J; Centre de Recherche Saint-Antoine, Sorbonne Université, Inserm, Paris, France., Cauzac M; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France., Pagesy P; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France., Gautheron J; Centre de Recherche Saint-Antoine, Sorbonne Université, Inserm, Paris, France., Desdouets C; Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France., Guilmeau S; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France., Issad T; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France., Postic C; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France.
Jazyk:	angličtina
Zdroj:	JHEP reports : innovation in hepatology [JHEP Rep] 2023 Aug 12; Vol. 6 (2), pp. 100878. Date of Electronic Publication: 2023 Aug 12 (Print Publication: 2024).
DOI:	10.1016/j.jhepr.2023.100878
Abstrakt:	Background & Aims: O -GlcNAcylation is a reversible post-translational modification controlled by the activity of two enzymes, O -GlcNAc transferase (OGT) and O -GlcNAcase (OGA). In the liver, O -GlcNAcylation has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease. Methods: To address whether OGT acts as a critical hepatic nutritional node, mice with a constitutive hepatocyte-specific deletion of OGT (OGT LKO ) were generated and challenged with different carbohydrate- and lipid-containing diets. Results: Analyses of 4-week-old OGT LKO mice revealed significant oxidative and endoplasmic reticulum stress, and DNA damage, together with inflammation and fibrosis, in the liver. Susceptibility to oxidative and endoplasmic reticulum stress-induced apoptosis was also elevated in OGT LKO hepatocytes. Although OGT expression was partially recovered in the liver of 8-week-old OGT LKO mice, hepatic injury and fibrosis were not rescued but rather worsened with time. Interestingly, weaning of OGT LKO mice on a ketogenic diet (low carbohydrate, high fat) fully prevented the hepatic alterations induced by OGT deletion, indicating that reduced carbohydrate intake protects an OGT-deficient liver. Conclusions: These findings pinpoint OGT as a key mediator of hepatocyte homeostasis and survival upon carbohydrate intake and validate OGT LKO mice as a valuable model for assessing therapeutical approaches of advanced liver fibrosis. Impact and Implications: Our study shows that hepatocyte-specific deletion of O -GlcNAc transferase (OGT) leads to severe liver injury, reinforcing the importance of O -GlcNAcylation and OGT for hepatocyte homeostasis and survival. Our study also validates the Ogt liver-deficient mouse as a valuable model for the study of advanced liver fibrosis. Importantly, as the severe hepatic fibrosis of Ogt liver-deficient mice could be fully prevented upon feeding on a ketogenic diet ( i.e. very-low-carbohydrate, high-fat diet) this work underlines the potential interest of nutritional intervention as antifibrogenic strategies. Competing Interests: The authors declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details. (.)
Databáze:	MEDLINE
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