Journal article
Acetate controls endothelial-to-mesenchymal transition
Cell metabolism, Vol.35(7), pp.1163-1178.e10
07/11/2023
DOI: 10.1016/j.cmet.2023.05.010
PMID: 37327791
Abstract
Endothelial-to-mesenchymal transition (EndMT), a process initiated by activation of endothelial TGF-(3 signaling, underlies numerous chronic vascular diseases and fibrotic states. Once induced, EndMT leads to a further increase in TGF-(3 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-(3-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-(3-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-(3 receptor ALK5 and SMADs 2 and 4 leading to activation and long-term stabilization of TGF-(3 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.
Details
- Title: Subtitle
- Acetate controls endothelial-to-mesenchymal transition
- Creators
- Xiaolong Zhu - Yale UniversityYunyun Wang - Sir Run Run Shaw HospitalIoana Soaita - University of PennsylvaniaHeon-Woo Lee - Yale UniversityHosung Bae - University of California, IrvineNabil Boutagy - Yale UniversityAnna Bostwick - Temple UniversityRong-Mo Zhang - Yale UniversityCaitlyn Bowman - University of PennsylvaniaYanying Xu - Central South UniversitySophie Trefely - Babraham InstituteYu Chen - Sir Run Run Shaw HospitalLingfeng Qin - Yale UniversityWilliam Sessa - Yale UniversityGeorge Tellides - Yale UniversityCholsoon Jang - University of California, IrvineNathaniel W. Snyder - Temple UniversityLuyang Yu - Sir Run Run Shaw HospitalZoltan Arany - University of PennsylvaniaMichael Simons - Yale University
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.35(7), pp.1163-1178.e10
- DOI
- 10.1016/j.cmet.2023.05.010
- PMID
- 37327791
- NLM abbreviation
- Cell Metab
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Publisher
- Elsevier
- Number of pages
- 27
- Grant note
- 91839104; 81770444 / National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) R01 HL135582; HL162887; DK135958; T32GM007229; F31HL158152 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 2018YFA0800504 / National Key Ramp;D Program of China Open Philanthropy Foundation BB/P013406/1 / Biotechnology and Biological Sciences Research Council (BBSRC); UK Research & Innovation (UKRI)
- Language
- English
- Date published
- 07/11/2023
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985217031402771
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