Liver TET1 promotesmetabolic dysfunction-associated steatotic liver disease by upregulating CD36

Background and Aims: The formation of 5-hydroxymethylcytosine catalyzed by the ten-eleven translocation (TET) methylcytosine dioxygenases is related to DNA demethylation and has been found decreased in human chronic liver diseases, including the metabolic dysfunction-associated steatotic liver disease (MASLD). However, the underlying mechanisms by which these enzymes are involved in MASLD progression are not clear. We aimed to determine how TET dioxygenases affect MASLD progression. We investigated the impacts of hepatic TET1 on MASLD. Approaches: Two strains of whole body TET1 knockout (KO) mice were generated and challenged with a high-fat diet (HFD). RNA sequencing (RNA-Seq) was used to clarify the TET1-mediated signaling cascades involved in MASLD. Liver specific TET1 KO mice were used to determine the role of hepatic TET1 in MASLD. A TET1 small molecule inhibitor was adopted to investigate the impacts of targeting TET1 in a preclinical MASLD model. Results: Whole body TET1 KO using two different strategies both substantially alleviated MASLD progression in a MASLD murine model induced with HFD feeding. Besides, TET1 KO led to reduced hepatic cholesterols, triglycerides, and circulating cholesterols in MASLD mice. However, fed glucose levels were not significantly impacted by TET1 KO. The RNA-Seq results revealed that CD36 and IGFBP2 were among the most significantly altered hepatic genes in TET1 KO mice fed with HFD. Inhibiting TET1 in human hepatocytes validated that CD36 is downregulated upon TET1 knockdown. Using the liver specific TET1 KO (TET1 LKO) mice, it was found that depleting hepatic TET1 protects mice from MASLD progression. The molecular mechanism studies determined that TET1 promoted CD36 expression through transcriptional up-regulation via binding to the CD36 enhancer regions. TET1 enzymatic function is required for CD36 upregulation. The effects of TET1 knockdown on fatty acid uptake were rescued by CD36 overexpression in human hepatocytes. More importantly, suppressing TET1 function with a small molecule inhibitor significantly improved MASLD progression in a preclinical MASLD model. Conclusions: Hepatic TET1 is likely involved in exacerbating MASLD progression, suggesting the potential of targeting TET1 signaling cascade in treating MASLD patients. R01DK135664 R21AA028576 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.