Related Experiment Video
Updated: Jan 4, 2026
Incorporation of a Survivable Liver Biopsy Procedure in Mice to Assess Non-alcoholic Steatohepatitis NASH Resolution
Published on: April 16, 2019
O-GlcNAc transferase suppresses necroptosis and liver fibrosis
Bichen Zhang1, Min-Dian Li1, Ruonan Yin2
1Department of Cellular and Molecular Physiology and.
Abstract:
Worldwide, over a billion people suffer from chronic liver diseases, which often lead to fibrosis and then cirrhosis. Treatments for fibrosis remain experimental, in part because no unifying mechanism has been identified that initiates liver fibrosis. Necroptosis has been implicated in multiple liver diseases. Here, we report that O-linked β-N-acetylglucosamine (O-GlcNAc) modification protects against hepatocyte necroptosis and initiation of liver fibrosis. Decreased O-GlcNAc levels were seen in patients with alcoholic liver cirrhosis and in mice with ethanol-induced liver injury. Liver-specific O-GlcNAc transferase-KO (OGT-LKO) mice exhibited hepatomegaly and ballooning degeneration at an early age and progressed to liver fibrosis and portal inflammation by 10 weeks of age. OGT-deficient hepatocytes underwent excessive necroptosis and exhibited elevated protein expression levels of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), which are key mediators of necroptosis. Furthermore, glycosylation of RIPK3 by OGT is associated with reduced RIPK3 protein stability. Taken together, these findings identify OGT as a key suppressor of hepatocyte necroptosis, and OGT-LKO mice may serve as an effective spontaneous genetic model of liver fibrosis.
Insights
O-linked β-N-acetylglucosamine (O-GlcNAc) modification prevents liver fibrosis by inhibiting necroptosis. Reduced O-GlcNAc levels in liver disease patients and OGT-deficient mice highlight OGT
Area of Science:
- Hepatology
- Molecular Biology
- Biochemistry
Background:
- Chronic liver diseases affect over a billion people globally, often progressing to fibrosis and cirrhosis.
- Current treatments for liver fibrosis are experimental due to an unidentified initiating mechanism.
- Necroptosis, a form of programmed cell death, is implicated in various liver pathologies.
Purpose of the Study:
- To investigate the role of O-linked β-N-acetylglucosamine (O-GlcNAc) modification in hepatocyte necroptosis and liver fibrosis.
- To determine if O-GlcNAc modification protects against the initiation of liver fibrosis.
- To explore the potential of O-GlcNAc transferase (OGT) as a therapeutic target for liver fibrosis.
Main Methods:
- Analysis of O-GlcNAc levels in patients with alcoholic liver cirrhosis and mice with ethanol-induced liver injury.
- Generation and characterization of liver-specific O-GlcNAc transferase-knockout (OGT-LKO) mice.
- Assessment of necroptosis mediators (RIPK3, MLKL) and RIPK3 protein stability in OGT-deficient hepatocytes.
Main Results:
- Decreased O-GlcNAc levels were observed in patients and mice with liver disease.
- OGT-LKO mice developed hepatomegaly, ballooning degeneration, liver fibrosis, and portal inflammation.
- OGT-deficient hepatocytes showed increased necroptosis, elevated RIPK3 and MLKL, and reduced RIPK3 protein stability due to OGT glycosylation.
Conclusions:
- O-GlcNAc modification, mediated by OGT, is a critical suppressor of hepatocyte necroptosis.
- Reduced OGT activity promotes liver fibrosis initiation.
- OGT-LKO mice represent a valuable spontaneous genetic model for studying liver fibrosis.
