期刊
CELL METABOLISM
卷 28, 期 6, 页码 881-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2018.07.016
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资金
- Research Foundation Flanders (FWO)
- Leopoldina Postdoc Scholarship
- Marie Curie-IEF Fellowship
- Fritz Thyssen Stiftung
- British Heart Foundation Intermediate Clinical Fellowship [FS/12/80/29821]
- Swiss National Science Foundation, Switzerland [BSCGI0_157859]
- Marie Curie CIG from the Research Foundation Flanders (FWO-Vlaanderen), Belgium
- VIB Tech-Watch program
- Federal Government Belgium [IUAP7/03]
- Flemish Government
- Research Foundation Flanders (FWO-Vlaanderen)
- Foundation against Cancer [2012-175, 2016-078]
- ERC Advanced Research grant [EU-ERC743074]
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center at the Sun Yat-Sen University
- National Natural Science Foundation of China [81330021, 81670855]
Little is known about the metabolism of quiescent endothelial cells (QECs). Nonetheless, when dysfunctional, QECs contribute to multiple diseases. Previously, we demonstrated that proliferating endothelial cells (PECs) use fatty acid beta-oxidation (FAO) for de novo dNTP synthesis. We report now that QECs are not hypometabolic, but upregulate FAO >3-fold higher than PECs, not to support biomass or energy production but to sustain the tricarboxylic acid cycle for redox homeostasis through NADPH regeneration. Hence, endothelial loss of FAO-controlling CPT1A in CPT1A(Delta EC) mice promotes EC dysfunction (leukocyte infiltration, barrier disruption) by increasing endothelial oxidative stress, rendering CPT1A(Delta EC) mice more susceptible to LPS and inflammatory bowel disease. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-coenzyme A) restores endothelial quiescence and counters oxidative stress-mediated EC dysfunction in CPT1A(Delta EC) mice, offering therapeutic opportunities. Thus, QECs use FAO for vasculoprotection against oxidative stress-prone exposure.
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