小柯机器人

美国耶鲁大学医学院Michael Simons，美国宾夕法尼亚大学Zoltan Arany和浙江大学Luyang Yu共同合作，近期取得重要工作进展。他们研究发现，乙酸盐可以控制内皮细胞向间充质细胞的转变。相关研究成果2023年6月15日在线发表于《细胞—代谢》杂志上。

据介绍，内皮-间充质转化（EndMT）是一个由内皮转化生长因子-β信号激活启动的过程，是许多慢性血管疾病和纤维化状态的基础。一旦诱导，EndMT导致TGF-β信号的进一步增加，从而与EndMT建立正反馈回路，导致更多的EndMT。尽管EndMT是在细胞水平上理解的，但TGF-β驱动的EndMT诱导和持续的分子基础在很大程度上仍然未知。

研究人员发现，由葡萄糖非典型产生乙酸盐触发的内皮代谢调节是TGF-β驱动的EndMT的基础。EndMT的诱导抑制了PDK4酶的表达，这导致从丙酮酸来源的乙酸盐合成ACSS2依赖性Ac-CoA的增加。这种增加的Ac-CoA产生导致TGF-β受体ALK5和SMAD 2和4的乙酰化，从而导致TGF-β信号的激活和长期稳定。

总之，这一研究结果建立了EndMT持久性的代谢基础，并揭示了新的靶点，如ACSS2，用于潜在的慢性血管疾病治疗。

附：英文原文

Title: Acetate controls endothelial-to-mesenchymal transition

Author: Xiaolong Zhu, Yunyun Wang, Ioana Soaita, Heon-Woo Lee, Hosung Bae, Nabil Boutagy, Anna Bostwick, Rong-Mo Zhang, Caitlyn Bowman, Yanying Xu, Sophie Trefely, Yu Chen, Lingfeng Qin, William Sessa, George Tellides, Cholsoon Jang, Nathaniel W. Snyder, Luyang Yu, Zoltan Arany, Michael Simons

Issue&Volume: 2023-06-15

Abstract: Endothelial-to-mesenchymal transition (EndMT), a process initiated by activation ofendothelial TGF-β signaling, underlies numerous chronic vascular diseases and fibroticstates. Once induced, EndMT leads to a further increase in TGF-β signaling, thus establishinga positive-feedback loop with EndMT leading to more EndMT. Although EndMT is understoodat the cellular level, the molecular basis of TGF-β-driven EndMT induction and persistenceremains largely unknown. Here, we show that metabolic modulation of the endothelium,triggered by atypical production of acetate from glucose, underlies TGF-β-driven EndMT.Induction of EndMT suppresses the expression of the enzyme PDK4, which leads to anincrease in ACSS2-dependent Ac-CoA synthesis from pyruvate-derived acetate. This increasedAc-CoA production results in acetylation of the TGF-β receptor ALK5 and SMADs 2 and4 leading to activation and long-term stabilization of TGF-β signaling. Our resultsestablish the metabolic basis of EndMT persistence and unveil novel targets, suchas ACSS2, for the potential treatment of chronic vascular diseases.

DOI: 10.1016/j.cmet.2023.05.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00203-6

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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