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Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice
Robarts, Dakota R. McGreal, Steven R. Umbaugh, David S. Parkes, Wendena S. Kotulkar, Manasi Abernathy, Sarah Lee, Norman Jaeschke, Hartmut Gunewardena, Sumedha Whelan, Stephen A.
Robarts, Dakota R.
McGreal, Steven R.
Umbaugh, David S.
Parkes, Wendena S.
Kotulkar, Manasi
Abernathy, Sarah
Lee, Norman
Jaeschke, Hartmut
Gunewardena, Sumedha
Whelan, Stephen A.
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Abstract
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.
Description
A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.
Date
2022-01-01
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Elsevier
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Citation
Robarts, D.R., et al., 2022. Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice. Cellular and Molecular Gastroenterology and Hepatology. vol. 13, no. 5, pp. 1510-1529. DOI: 10.1016/j.jcmgh.2022.01.014.