HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Nat Commun. 2022 Aug 4;13(1):4549. doi: 10.1038/s41467-022-32163-w.
Ectopic lipid accumulation and inflammation are the essential signs of NASH. However, the molecular mechanisms of ectopic lipid accumulation and inflammation during NASH progression are not fully understood. Here we reported that hepatic Wilms' tumor 1-associating protein (WTAP) is a key integrative regulator of ectopic lipid accumulation and inflammation during NASH progression. Hepatic deletion of Wtap leads to NASH due to the increased lipolysis in white adipose tissue, enhanced hepatic free fatty acids uptake and induced inflammation, all of which are mediated by IGFBP1, CD36 and cytochemokines such as CCL2, respectively. WTAP binds to specific DNA motifs which are enriched in the promoters and suppresses gene expression (e.g., Igfbp1, Cd36 and Ccl2) with the involvement of HDAC1. In NASH, WTAP is tranlocated from nucleus to cytosol, which is related to CDK9-mediated phosphorylation. These data uncover a mechanism by which hepatic WTAP regulates ectopic lipid accumulation and inflammation during NASH progression.
异位脂质积累和炎症是 NASH 的重要标志。然而，NASH 进展过程中异位脂质积累和炎症的分子机制尚不完全清楚。在这里，我们报道了肝母细胞瘤 1 相关蛋白（WTAP）是 NASH 进展过程中异位脂质积累和炎症的关键综合调节因子。肝 WTAP 的缺失导致 NASH，原因是白色脂肪组织中的脂肪分解增加，肝内游离脂肪酸摄取增强，并诱导炎症，所有这些都是由 IGFBP1、CD36 和趋化因子（如 CCL2）介导的。WTAP 与富含启动子并抑制基因表达的特定 DNA 基序结合（例如 Igfbp1、Cd36 和 Ccl2），涉及 HDAC1。在 NASH 中，WTAP 从核转位到细胞质，这与 CDK9 介导的磷酸化有关。这些数据揭示了肝 WTAP 调节 NASH 进展过程中异位脂质积累和炎症的机制。
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