| First Author | Zhu X | Year | 2023 |
| Journal | Cell Metab | Volume | 35 |
| Issue | 7 | Pages | 1163-1178.e10 |
| PubMed ID | 37327791 | Mgi Jnum | J:338352 |
| Mgi Id | MGI:7511285 | Doi | 10.1016/j.cmet.2023.05.010 |
| Citation | Zhu X, et al. (2023) Acetate controls endothelial-to-mesenchymal transition. Cell Metab 35(7):1163-1178.e10 |
| abstractText | Endothelial-to-mesenchymal transition (EndMT), a process initiated by activation of endothelial TGF-beta signaling, underlies numerous chronic vascular diseases and fibrotic states. Once induced, EndMT leads to a further increase in TGF-beta signaling, thus establishing a positive-feedback loop with EndMT leading to more EndMT. Although EndMT is understood at the cellular level, the molecular basis of TGF-beta-driven EndMT induction and persistence remains largely unknown. Here, we show that metabolic modulation of the endothelium, triggered by atypical production of acetate from glucose, underlies TGF-beta-driven EndMT. Induction of EndMT suppresses the expression of the enzyme PDK4, which leads to an increase in ACSS2-dependent Ac-CoA synthesis from pyruvate-derived acetate. This increased Ac-CoA production results in acetylation of the TGF-beta receptor ALK5 and SMADs 2 and 4 leading to activation and long-term stabilization of TGF-beta signaling. Our results establish the metabolic basis of EndMT persistence and unveil novel targets, such as ACSS2, for the potential treatment of chronic vascular diseases. |
