OGT Is Crucial for Hepatocyte Survival and Liver Homeostasis Through the Control of Oxidative Stress

To address the role of O-GlcNAc transferase (OGT) in hepatocytes, the key enzyme of O-GlcNAcylation, we generated mice with a hepatocyte-specific deletion of OGT (OGT∆). Four weeks after birth, OGT∆ mice presented liver inflammation, oxidative stress, increased expression of ER stress and DNA damage markers, together with a decrease in O-GlcNAcylation of NRF1 and FoxO1, two key modulators of oxidative stress. In addition, OGT∆ hepatocytes were more sensitive to apoptosis when treated with staurosporine, an inducer of oxidative stress. The OGT∆ phenotype worsened with the presence of liver fibrosis septa surrounding regeneration nodules, associated with a significant increase in proliferation and inflammation markers. Interestingly, OGT expression was recovered in liver of 8 week-old OGT∆ mice suggesting counter-selection against OGT deficient cells. OGT recovery correlated with improvement of the hepatic oxidative phenotype, suggesting that OGT plays an essential role in hepatocyte survival and liver homeostasis through the control of oxidative stress.