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
Affiliations
Paula Ortega-Prieto
Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
Lucia Parlati
Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
Fadila Benhamed
Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
Marion Regnier
Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
Isadora Cavalcante
Team Genomics and Signaling of Endocrine Tumors, Institut Cochin, CNRS, INSERM, Université Paris Cité, Paris, France
Mélanie Montabord
Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
Rachel Onifarasoaniaina
HistIM Platform, Institut Cochin, CNRS, INSERM, Université de Paris Cité, Paris, France
Maryline Favier
HistIM Platform, Institut Cochin, CNRS, INSERM, Université de Paris Cité, Paris, France
Natasa Pavlovic
Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
Julie Magusto
Centre de Recherche Saint-Antoine, Sorbonne Université, Inserm, Paris, France
Michèle Cauzac
Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
Patrick Pagesy
Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
Jérémie Gautheron
Centre de Recherche Saint-Antoine, Sorbonne Université, Inserm, Paris, France
Chantal Desdouets
Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
Sandra Guilmeau
Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
Tarik Issad
Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France; Corresponding authors. Address: Institut Cochin, Inserm U101624, Rue du Faubourg Saint Jacques 75014 Paris, France. Tel.: +33 685849052 (C. Postic); +33 1 44412567 (T. Issad).
Catherine Postic
Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France; Corresponding authors. Address: Institut Cochin, Inserm U101624, Rue du Faubourg Saint Jacques 75014 Paris, France. Tel.: +33 685849052 (C. Postic); +33 1 44412567 (T. Issad).
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 (OGTLKO) were generated and challenged with different carbohydrate- and lipid-containing diets. Results: Analyses of 4-week-old OGTLKO 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 OGTLKO hepatocytes. Although OGT expression was partially recovered in the liver of 8-week-old OGTLKO mice, hepatic injury and fibrosis were not rescued but rather worsened with time. Interestingly, weaning of OGTLKO 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 OGTLKO 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.
