Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice

• DOI: 10.1016/j.jcmgh.2022.01.014
• Publication Date: 2022-01-28T10:34:27Z
• Authors: 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
• Keywords: Liver Regeneration; Hepatocyte nuclear factors

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