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    Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice

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    Issue Date
    2022-01-01
    Author
    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.
    Hanover, John A.
    Zachara, Natasha E.
    Slawson, Chad
    Apte, Udayan
    Publisher
    Elsevier
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
    Rights
    Copyright © 2022 The Authors.
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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.
    URI
    http://hdl.handle.net/1808/33665
    DOI
    https://doi.org/10.1016/j.jcmgh.2022.01.014
    Collections
    • KU Scholarly Papers Funded by the KU Open Access Fund [213]
    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.

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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