Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice

Dakota R. Robarts, Steven R. McGreal, David S. Umbaugh, Wendena S. Parkes, Manasi Kotulkar, Sarah Abernathy, Norman Lee, Hartmut Jaeschke, Sumedha Gunewardena, Stephen A. Whelan, John A. Hanover, Natasha E. Zachara, Chad Slawson, Udayan Apte

Research output: Contribution to journalArticlepeer-review


Background & Aims: The liver has a unique capacity to regenerate after injury in a highly orchestrated and regulated manner. Here, we report that O-GlcNAcylation, an intracellular post-translational modification regulated by 2 enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), is a critical termination signal for liver regeneration following partial hepatectomy (PHX). Methods: We studied liver regeneration after PHX on hepatocyte specific OGT and OGA knockout mice (OGT-KO and OGA-KO), which caused a significant decrease (OGT-KO) and increase (OGA-KO) in hepatic O-GlcNAcylation, respectively. Results: OGA-KO mice had normal regeneration, but the OGT-KO mice exhibited substantial defects in termination of liver regeneration with increased liver injury, sustained cell proliferation resulting in significant hepatomegaly, hepatic dysplasia, and appearance of small nodules at 28 days after PHX. This was accompanied by a sustained increase in expression of cyclins along with significant induction in pro-inflammatory and pro-fibrotic gene expression in the OGT-KO livers. RNA-sequencing studies revealed inactivation of hepatocyte nuclear 4 alpha (HNF4α), the master regulator of hepatic differentiation and a known termination signal, in OGT-KO mice at 28 days after PHX, which was confirmed by both Western blot and immunohistochemistry analysis. Furthermore, a significant decrease in HNFα target genes was observed in OGT-KO mice, indicating a lack of hepatocyte differentiation following decreased hepatic O-GlcNAcylation. Immunoprecipitation experiments revealed HNF4α is O-GlcNAcylated in normal differentiated hepatocytes. Conclusions: These studies show that O-GlcNAcylation plays a critical role in the termination of liver regeneration via regulation of HNF4α in hepatocytes.

Original languageEnglish (US)
Pages (from-to)1510-1529
Number of pages20
Issue number5
StatePublished - Jan 2022


  • Cell Death
  • HNF4alpha
  • Partial Hepatectomy
  • Proliferation
  • Regeneration

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology


Dive into the research topics of 'Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice'. Together they form a unique fingerprint.

Cite this