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

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.

Graphical abstract

Highlights

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  O-GlcNAcylation is a reversible post-translational modification controlled by the activity of two enzymes, OGT and OGA.

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  In the liver, O-GlcNAcylation has emerged as an important regulatory mechanism.

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  OGT deficiency was associated with hepatic oxidative stress and DNA damage, as well as inflammation and advanced fibrosis.

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  A nutritional switch at weaning (lowering carbohydrate intake) prevented the hepatic alteration caused by OGT deficiency.

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  Our study reveals that OGT acts as an important nutritional sensor in the liver.