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

Paula Ortega-Prieto; Lucia Parlati; Fadila Benhamed; Marion Regnier; Isadora Cavalcante; Mélanie Montabord; Rachel Onifarasoaniaina; Maryline Favier; Natasa Pavlovic; Julie Magusto; Michèle Cauzac; Patrick Pagesy; Jérémie Gautheron; Chantal Desdouets; Sandra Guilmeau; Tarik Issad; Catherine Postic

doi:10.1016/j.jhepr.2023.100878

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

JHEP Rep. 2023 Aug 12;6(2):100878. doi: 10.1016/j.jhepr.2023.100878. eCollection 2024 Feb.

Authors

Paula Ortega-Prieto¹, Lucia Parlati¹, Fadila Benhamed¹, Marion Regnier¹, Isadora Cavalcante², Mélanie Montabord¹, Rachel Onifarasoaniaina³, Maryline Favier³, Natasa Pavlovic⁴, Julie Magusto⁵, Michèle Cauzac¹, Patrick Pagesy¹, Jérémie Gautheron⁵, Chantal Desdouets⁴, Sandra Guilmeau¹, Tarik Issad¹, Catherine Postic¹

Affiliations

¹ Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France.
² Team Genomics and Signaling of Endocrine Tumors, Institut Cochin, CNRS, INSERM, Université Paris Cité, Paris, France.
³ HistIM Platform, Institut Cochin, CNRS, INSERM, Université de Paris Cité, Paris, France.
⁴ Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France.
⁵ Centre de Recherche Saint-Antoine, Sorbonne Université, Inserm, Paris, France.

Abstract

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.

Keywords: Carbohydrate intake; Ketogenic diet; Liver fibrosis; OGT; Oxidative stress.

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