Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice
Autor: | S. A. Whelan, M. Kotulkar, Chad Slawson, N. Lee, Hartmut Jaeschke, W. S. Parkes, S. Abernathy, D. S. Umbaugh, D. R. Robarts, Sumedha Gunewardena, S. R. McGreal, Natasha E. Zachara, John A. Hanover, Udayan Apte |
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Rok vydání: | 2021 |
Předmět: |
Liver injury
Hepatocyte differentiation Mice Knockout Hepatology Chemistry Regeneration (biology) Gastroenterology medicine.disease Liver regeneration Cell biology Liver Regeneration Mice medicine.anatomical_structure Hepatocyte nuclear factor 4 Liver Hepatocyte Knockout mouse Gene expression medicine Hepatocytes Animals Hepatectomy |
Zdroj: | Cellular and molecular gastroenterology and hepatology. 13(5) |
ISSN: | 2352-345X |
Popis: | 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 (PTM) regulated by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), is a critical termination signal for liver regeneration (LR) following partial hepatectomy (PHX). 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. 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-Seq 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 IHC 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. These studies show that O-GlcNAcylation plays a critical role in the termination of LR via regulation of HNF4α in hepatocytes.Layman summaryO-GlcNAcylation is a protein modification that plays a critical role in various biological processes including cell proliferation, differentiation, and disease progression. These studies show that O-GlcNAcylation in hepatocytes is essential for proper liver regeneration. Without O-GlcNAcylation, hepatocytes keep on proliferating eventually forming liver tumors. |
Databáze: | OpenAIRE |
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