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Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice

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 criti...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9043307/
https://www.ncbi.nlm.nih.gov/pubmed/35093590
http://dx.doi.org/10.1016/j.jcmgh.2022.01.014
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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
author_facet 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
author_sort Robarts, Dakota R.
collection PubMed
description 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.
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spelling pubmed-90433072022-04-28 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. Hanover, John A. Zachara, Natasha E. Slawson, Chad Apte, Udayan Cell Mol Gastroenterol Hepatol Original Research 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. Elsevier 2022-01-28 /pmc/articles/PMC9043307/ /pubmed/35093590 http://dx.doi.org/10.1016/j.jcmgh.2022.01.014 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
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
Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice
title Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice
title_full Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice
title_fullStr Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice
title_full_unstemmed Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice
title_short Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice
title_sort regulation of liver regeneration by hepatocyte o-glcnacylation in mice
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9043307/
https://www.ncbi.nlm.nih.gov/pubmed/35093590
http://dx.doi.org/10.1016/j.jcmgh.2022.01.014
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