Chen Hongze, Nisar Muhammad Azhar, Mulla Joud, Li Xinjian, Cao Kevin, Lu Shaolei, Nagaoka Katsuya, Wu Shang, Ting Peng-Sheng, Tseng Tung-Sung, Lin Hui-Yi, Yin Xiao-Ming, Feng Wenke, Wu Zhijin, Cheng Zhixiang, Mueller William, Bay Amalia, Schechner Layla, Bai Xuewei, Huang Chiung-Kuei
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang Province, China.
EMBO Mol Med. 2025 May;17(5):1101-1117. doi: 10.1038/s44321-025-00224-4. Epub 2025 Mar 31.
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.
全球肝脏DNA甲基化变化与患有代谢功能障碍相关脂肪性肝病（MASLD）的人类患者有关。DNA去甲基化由TET家族蛋白调节，其酶活性需要2-氧代戊二酸（2-OG）和铁，而这两者在人类MASLD患者中均升高。我们旨在研究肝脏TET1在MASLD进展中的作用。使用两种不同策略耗尽TET1可显著减轻MASLD进展。敲除（KO）TET1可轻微改善饮食诱导的肥胖和葡萄糖稳态。有趣的是，TET1耗尽后，肝脏胆固醇、甘油三酯和CD36显著降低。同样，肝脏特异性TET1基因敲除可改善MASLD进展。从机制上讲，TET1通过DNA去甲基化控制转录上调来促进CD36表达。CD36的过表达逆转了TET1下调对肝细胞脂肪酸摄取的影响。更重要的是，用小分子抑制剂靶向TET1可显著抑制MASLD进展。总之，肝脏TET1在MASLD中起有害作用，这表明靶向肝细胞中的TET1以抑制MASLD的潜力。
