O-Glcnacylation: The Switch Between Termination Of Regeneration And Initiation Of Hepatic Dysplasia

BackgroundO‐GlcNAcylation is a posttranslational modification where a single N‐acetyl glucosamine (O‐GlcNAc) sugar is added to Ser/Thr residue of a protein catalyzed by an enzyme called GlcNAc transferase (OGT). O‐GlcNAcylation plays a significant role in cell proliferation, signaling and cancer pathogenesis. We investigated the role of O‐GlcNAcylation in liver regeneration after partial hepatectomy (PH) using hepatocyte specific OGT knockout (OGTKO) mice.MethodsTwo‐three month old male WT and OGTKO mice were subjected to PH and samples were collected over a time course of 0 to 28 days after surgery. Liver regeneration was determined using liver to body weight ratio, H&E staining; PCNA immunohistochemistry, and Western blot for proteins critical to cell cycle progression. RNAseq studies were performed to identify global gene expression changes.ResultsWT mice had a normal regenerative response with peak proliferation at 48 hr after PH and the lost liver mass was regained within 14 days. OGT KO mice showed significantly faster regeneration as demonstrated by a rapid return to pre‐PHX liver to body weight ratio as compared to WT mice. OGT KO mice also showed significantly higher cell proliferation than WT mice at 5, 7, and 14 days, which continued till 28 days after PH. At 28 days after PH, the OGT KO liver showed significant histopathological abnormalities including giant cells, abnormal mitoses, significant intracellular globule accumulation and extensive ductular reaction. Morphometric analysis revealed that OGTKO hepatocytes and hepatocyte nuclei were significantly larger than WT cells. Most strikingly, the OGTKO mice showed several small dysplastic nodules at 28 day after PH. The increased proliferation was accompanied by significant induction of cell cycle regulators such as Cyclin D1 and pRb. RNAseq data revealed that OGTKO livers had a promitogenic and dedifferentiated gene expression profile consistent with histopathological changes. Finally, OGTKO mice has significant downregulation of HNF4aexpression and Co‐IP studies revealed that HNF4ais O‐GlcNAcylated in WT mice.ConclusionsThese data show that loss of O‐GlcNAcylation secondary to deletion of OGT results in uncontrolled hepatocyte proliferation and failed redifferentiation leading to dysplasia following PH. O‐GlcNAcylation is a major regulator of cell proliferation during termination of liver regeneration and disruption in cellular O‐GlcNac status may promote hepatocarcinogenesis.Support or Funding InformationNIH R01 DK098414This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.