Document Type
Article
Publication Date
3-31-2025
Publication Title
EMBO Molecular Medicine
Abstract
Global hepatic DNA methylation change has been linked to human patients with metabolic dysfunction-associated steatotic liver disease (MASLD). DNA demethylation is regulated by the TET family proteins, whose enzymatic activities require 2-oxoglutarate (2-OG) and iron that both are elevated in human MASLD patients. We aimed to investigate liver TET1 in MASLD progression. Depleting TET1 using two different strategies substantially alleviated MASLD progression. Knockout (KO) of TET1 slightly improved diet induced obesity and glucose homeostasis. Intriguingly, hepatic cholesterols, triglycerides, and CD36 were significantly decreased upon TET1 depletion. Consistently, liver specific TET1 KO led to improvement of MASLD progression. Mechanistically, TET1 promoted CD36 expression through transcriptional upregulation via DNA demethylation control. Overexpression of CD36 reversed the impacts of TET1 downregulation on fatty acid uptake in hepatocytes. More importantly, targeting TET1 with a small molecule inhibitor significantly suppressed MASLD progression. Conclusively, liver TET1 plays a deleterious role in MASLD, suggesting the potential of targeting TET1 in hepatocytes to suppress MASLD.
PubMed ID
40164757
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Chen, Hongze; Nisar, Muhammad Azhar; Mulla, Joud; Li, Xinjian; Cao, Kevin; Lu, Shaolei; Nagaoka, Katsuya; Wu, Shang; Ting, Peng Sheng; Tseng, Tung Sung; Lin, Hui Yi; Yin, Xiao Ming; Feng, Wenke; Wu, Zhijin; Cheng, Zhixiang; Mueller, William; Bay, Amalia; Schechner, Layla; Bai, Xuewei; and Huang, Chiung Kuei, "Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease" (2025). School of Public Health Faculty Publications. 487.
https://digitalscholar.lsuhsc.edu/soph_facpubs/487
10.1038/s44321-025-00224-4
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Biostatistics Commons, Community Health Commons, Data Science Commons, Hepatology Commons, Medical Pathology Commons