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Updated: Mar 5, 2026
Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Published on: July 18, 2025
Global identification and analysis of isozyme-specific possible substrates crosslinked by transglutaminases using
Hideki Tatsukawa1, Yuji Tani1, Risa Otsu1
1Cellular Biochemistry Lab., Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan.
Abstract:
The transglutaminase (TG) family comprises eight isozymes that form the isopeptide bonds between glutamine and lysine residues and contribute to the fibrotic diseases via crosslinking-mediated stabilization of ECM and the activation of TGF-β in several tissues. However, despite a growing body of evidence implicating TG2 as a key enzyme in fibrosis, the causative role of TG2 and the involvement of the other isozymes have not yet been fully elucidated. Therefore, here we clarified the distributions of TG isozymes and their in situ activities and identified the isozyme-specific possible substrates for both TG1 and TG2 using their substrate peptides in mouse fibrotic liver. We found that TG1 activity was markedly enhanced intracellularly over a widespread area, whereas TG2 activity increased in the extracellular space. In total, 43 and 42 possible substrates were identified for TG1 and TG2, respectively, as involved in chromatin organization and cellular component morphogenesis. These included keratin 18, a biomarker for hepatic injury, which was accumulated in the fibrotic liver and showed the partly similar distribution with TG1 activity. These findings suggest that TG1 activity may be involved in the functional modification of intracellular proteins, whereas TG2 activity contributes to the stabilization of extracellular proteins during liver fibrosis.
Insights
Transglutaminase (TG) enzyme activity, particularly TG1 and TG2, is altered in liver fibrosis. TG1 is mainly intracellular, while TG2 is extracellular, suggesting distinct roles in fibrotic processes.
Area of Science:
- Biochemistry
- Cell Biology
- Pathology
Background:
- The transglutaminase (TG) enzyme family plays a role in fibrotic diseases through protein crosslinking and TGF-β activation.
- While TG2 is implicated in fibrosis, the roles of other TG isozymes remain unclear.
Purpose of the Study:
- To investigate the distribution and activity of TG isozymes in mouse fibrotic liver.
- To identify TG1 and TG2 specific substrates in liver fibrosis.
Main Methods:
- Analysis of TG isozyme distribution and in situ activity in mouse fibrotic liver models.
- Identification of TG1 and TG2 substrates using specific substrate peptides.
Main Results:
- TG1 activity was significantly increased intracellularly, whereas TG2 activity was enhanced in the extracellular space.
- 43 and 42 potential substrates were identified for TG1 and TG2, respectively, involved in chromatin organization and morphogenesis.
- Keratin 18, a marker of hepatic injury, showed a distribution pattern similar to TG1 activity in fibrotic liver.
Conclusions:
- TG1 may modify intracellular proteins, while TG2 contributes to extracellular protein stabilization during liver fibrosis.
- These findings highlight distinct intracellular and extracellular roles for TG1 and TG2 in the pathogenesis of liver fibrosis.
