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<p>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.</p>

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Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月31日

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  • Hongze Chen,
  • Muhammad Azhar Nisar,
  • Joud Mulla,
  • Xinjian Li,
  • Kevin Cao,
  • Shaolei Lu,
  • Katsuya Nagaoka,
  • Shang Wu,
  • Peng-Sheng Ting,
  • Tung-Sung Tseng,
  • Hui-Yi Lin,
  • Xiao-Ming Yin,
  • Wenke Feng,
  • Zhijin Wu,
  • Zhixiang Cheng,
  • William Mueller,
  • Amalia Bay,
  • Layla Schechner,
  • Xuewei Bai,
  • Chiung-Kuei Huang

摘要

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.