2. Academic Validation
  3. Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease

Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease

  • EMBO Mol Med. 2025 May;17(5):1101-1117. doi: 10.1038/s44321-025-00224-4.
Hongze Chen # 1 2,  Muhammad Azhar Nisar # 1,  Joud Mulla # 3,  Xinjian Li 1 2,  Kevin Cao 3,  Shaolei Lu 4,  Katsuya Nagaoka 3,  Shang Wu 1,  Peng-Sheng Ting 5,  Tung-Sung Tseng 6,  Hui-Yi Lin 6,  Xiao-Ming Yin 1,  Wenke Feng 7,  Zhijin Wu 8,  Zhixiang Cheng 3,  William Mueller 3,  Amalia Bay 3,  Layla Schechner 1,  Xuewei Bai 2 3,  Chiung-Kuei Huang 9
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
  • 2 Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang Province, China.
  • 3 Liver Research Center, Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI, USA.
  • 4 Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, USA.
  • 5 Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
  • 6 School of Public Health, Louisiana State University Health Sciences Center, New Orleans, USA.
  • 7 Department Structural Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.
  • 8 Department of Biostatistics, School of Public Health, Brown University, Providence, RI, USA.
  • 9 Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA. chuang17@tulane.edu.
  • # Contributed equally.
PMID: 40164757 DOI: 10.1038/s44321-025-00224-4
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.

Keywords

5-Hydroxymethylcytosine; Alcoholic Liver Disease; Epigenetics; Fatty Liver; Nonalcoholic Fatty Liver Disease.

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