Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease
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.
Authors
- Katsuya Nagaoka (ORCID: https://orcid.org/0000-0002-7152-6101)
- Chiung‐Kuei Huang (ORCID: https://orcid.org/0000-0001-6331-7898)
- Peng–Sheng Ting (ORCID: https://orcid.org/0000-0003-1581-2354)
- Joud Mulla (ORCID: https://orcid.org/0000-0002-3872-0404)
- Hui‐Yi Lin (ORCID: https://orcid.org/0000-0002-3307-5549)
- Hongze Chen (ORCID: https://orcid.org/0000-0002-4805-4150)
- William F. Mueller (ORCID: https://orcid.org/0000-0001-9134-7648)
- Kevin Cao
- Wenke Feng (ORCID: https://orcid.org/0000-0001-5456-5347)
- Muhammad Azhar Nisar (ORCID: https://orcid.org/0000-0003-3249-6365)
- Xuewei Bai (ORCID: https://orcid.org/0000-0001-8015-5464)
- Amalia Bay
- Shaolei Lu (ORCID: https://orcid.org/0000-0003-2870-5793)
- Zhixiang Cheng (ORCID: https://orcid.org/0000-0003-0867-685X)
- Tung‐Sung Tseng (ORCID: https://orcid.org/0000-0001-6266-9891)
- Xinjian Li (ORCID: https://orcid.org/0000-0001-5338-7112)
- Zhijin Wu (ORCID: https://orcid.org/0000-0002-9596-9134)
- Xiao-Ming Yin (ORCID: https://orcid.org/0000-0002-8576-6093)
- Shang Wu (ORCID: https://orcid.org/0009-0009-1870-4210)
- Layla Schechner
Institutions
- Tulane University (US)
- Harbin Medical University (CN)
- Brown University (US)
- Rhode Island Hospital (US)
- First Affiliated Hospital of Harbin Medical University (CN)
- Louisiana State University Health Sciences Center New Orleans (US)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-03-31
- DOI
- https://doi.org/10.1038/s44321-025-00224-4
- Citations
- 3
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- American Association for the Study of Liver Diseases
- National Institute on Alcohol Abuse and Alcoholism
- National Institute of General Medical Sciences
- Division of Diabetes, Endocrinology, and Metabolic Diseases