Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease
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...
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| Language: | English |
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Springer Nature
2025-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-025-00224-4 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hongze Chen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b6732128dc5d41b0af816eafa72177cc |
| institution | Kabale University |
| issn | 1757-4684 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-b6732128dc5d41b0af816eafa72177cc2025-08-20T03:48:02ZengSpringer NatureEMBO Molecular Medicine1757-46842025-03-011751101111710.1038/s44321-025-00224-4Liver TET1 promotes metabolic dysfunction-associated steatotic liver diseaseHongze Chen0Muhammad Azhar Nisar1Joud Mulla2Xinjian Li3Kevin Cao4Shaolei Lu5Katsuya Nagaoka6Shang Wu7Peng-Sheng Ting8Tung-Sung Tseng9Hui-Yi Lin10Xiao-Ming Yin11Wenke Feng12Zhijin Wu13Zhixiang Cheng14William Mueller15Amalia Bay16Layla Schechner17Xuewei Bai18Chiung-Kuei Huang19Department of Pathology and Laboratory Medicine, Tulane University School of MedicineDepartment of Pathology and Laboratory Medicine, Tulane University School of MedicineLiver Research Center, Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island HospitalDepartment of Pathology and Laboratory Medicine, Tulane University School of MedicineLiver Research Center, Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island HospitalDepartment of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Rhode Island HospitalLiver Research Center, Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island HospitalDepartment of Pathology and Laboratory Medicine, Tulane University School of MedicineDepartment of Medicine, Tulane University School of MedicineSchool of Public Health, Louisiana State University Health Sciences CenterSchool of Public Health, Louisiana State University Health Sciences CenterDepartment of Pathology and Laboratory Medicine, Tulane University School of MedicineDepartment Structural Cellular Biology, Tulane University School of MedicineDepartment of Biostatistics, School of Public Health, Brown UniversityLiver Research Center, Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island HospitalLiver Research Center, Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island HospitalLiver Research Center, Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island HospitalDepartment of Pathology and Laboratory Medicine, Tulane University School of MedicineDepartment of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical UniversityDepartment of Pathology and Laboratory Medicine, Tulane University School of MedicineAbstract 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.https://doi.org/10.1038/s44321-025-00224-4Fatty LiverAlcoholic Liver DiseaseNonalcoholic Fatty Liver DiseaseEpigenetics5-Hydroxymethylcytosine |
| spellingShingle | 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 Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease EMBO Molecular Medicine Fatty Liver Alcoholic Liver Disease Nonalcoholic Fatty Liver Disease Epigenetics 5-Hydroxymethylcytosine |
| title | Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease |
| title_full | Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease |
| title_fullStr | Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease |
| title_full_unstemmed | Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease |
| title_short | Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease |
| title_sort | liver tet1 promotes metabolic dysfunction associated steatotic liver disease |
| topic | Fatty Liver Alcoholic Liver Disease Nonalcoholic Fatty Liver Disease Epigenetics 5-Hydroxymethylcytosine |
| url | https://doi.org/10.1038/s44321-025-00224-4 |
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