O-GlcNAcylation: A key regulator of hepatic proliferation and differentiation
type: CreativeWork
description: O-GlcNAcylation is a posttranslational modification involved in various physiological processes, including development, regeneration, inflammation, proliferation, metabolism, and pathogenesis of various diseases. O-GlcNAcylation is regulated by two enzymes, O-GlcNAc transferase (OGT), which adds a glucosamine sugar on serine or threonine residues of proteins, and O-GlcNAcase (OGA), which removes the sugar molecule. The process of O-GlcNAcylation plays a role in regulating the cellular fate of various cell types, including hematopoietic stem cells and preadipocytes. In these studies, we demonstrated that O-GlcNAcylation regulates hepatic differentiation and liver regeneration and protects against the development of hepatocellular carcinoma (HCC). To investigate the role of O-GlcNAcylation in liver pathobiology, we studied mice with knockout (KO) of OGT or OGA specifically in hepatocytes, which led to a significant decrease or increase in hepatic O-GlcNAcylation, respectively. Our studies, aided by single-cell RNA sequencing, revealed that a decrease in hepatocyte O-GlcNAcylation resulted in loss of hepatic differentiation, specifically in the periportal hepatocytes and disruption of liver zonation. The lack of hepatic differentiation in OGT-KO mice was accompanied by cell death, increased inflammation, and the initiation of fibrosis. Further, we found that while OGA-KO mice had normal liver regeneration, OGT-KO mice exhibited defects in the termination of liver regeneration, resulting in sustained cell proliferation, significant hepatomegaly, hepatic dysplasia, and the appearance of small dysplastic nodules 28 days after PHX. These mice also showed sustained increases in the expression of cyclins, along with a significant induction of pro-inflammatory and pro-fibrotic gene expression in the liver. RNA-Seq studies revealed the inactivation of HNF4α, a known termination signal and master regulator of hepatic differentiation, in OGT-KO mice 28 days after PHX. This lack …
abstract: O-GlcNAcylation is a posttranslational modification involved in various physiological processes, including development, regeneration, inflammation, proliferation, metabolism, and pathogenesis of various diseases. O-GlcNAcylation is regulated by two enzymes, O-GlcNAc transferase (OGT), which adds a glucosamine sugar on serine or threonine residues of proteins, and O-GlcNAcase (OGA), which removes the sugar molecule. The process of O-GlcNAcylation plays a role in regulating the cellular fate of various cell types, including hematopoietic stem cells and preadipocytes. In these studies, we demonstrated that O-GlcNAcylation regulates hepatic differentiation and liver regeneration and protects against the development of hepatocellular carcinoma (HCC). To investigate the role of O-GlcNAcylation in liver pathobiology, we studied mice with knockout (KO) of OGT or OGA specifically in hepatocytes, which led to a significant decrease or increase in hepatic O-GlcNAcylation, respectively. Our studies, aided by single-cell RNA sequencing, revealed that a decrease in hepatocyte O-GlcNAcylation resulted in loss of hepatic differentiation, specifically in the periportal hepatocytes and disruption of liver zonation. The lack of hepatic differentiation in OGT-KO mice was accompanied by cell death, increased inflammation, and the initiation of fibrosis. Further, we found that while OGA-KO mice had normal liver regeneration, OGT-KO mice exhibited defects in the termination of liver regeneration, resulting in sustained cell proliferation, significant hepatomegaly, hepatic dysplasia, and the appearance of small dysplastic nodules 28 days after PHX. These mice also showed sustained increases in the expression of cyclins, along with a significant induction of pro-inflammatory and pro-fibrotic gene expression in the liver. RNA-Seq studies revealed the inactivation of HNF4α, a known termination signal and master regulator of hepatic differentiation, in OGT-KO mice 28 days after PHX. This lack …
author: Robarts, Dakota Ray
language: en
keywords: Toxicology, CDE Diet, HCC, HNF4alpha, Liver Regeneration, O-GlcNAc, Single-Cell RNA-Sequencing
date published: 2023-05-31
date modified: 2026-07-24T02:46:29Z
provider: University of Kansas
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Kansas

PropertyValue
property ID: Handle
value: https://hdl.handle.net/1808/37158