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- Title
α-Tocopherol-13′-Carboxychromanol Induces Cell Cycle Arrest and Cell Death by Inhibiting the SREBP1-SCD1 Axis and Causing Imbalance in Lipid Desaturation.
- Authors
Liao, Sijia; Gollowitzer, André; Börmel, Lisa; Maier, Charlotte; Gottschalk, Luisa; Werz, Oliver; Wallert, Maria; Koeberle, Andreas; Lorkowski, Stefan
- Abstract
α-Tocopherol-13′-carboxychromanol (α-T-13′-COOH) is an endogenously formed bioactive α-tocopherol metabolite that limits inflammation and has been proposed to exert lipid metabolism-regulatory, pro-apoptotic, and anti-tumoral properties at micromolar concentrations. The mechanisms underlying these cell stress-associated responses are, however, poorly understood. Here, we show that the induction of G0/G1 cell cycle arrest and apoptosis in macrophages triggered by α-T-13′-COOH is associated with the suppressed proteolytic activation of the lipid anabolic transcription factor sterol regulatory element-binding protein (SREBP)1 and with decreased cellular levels of stearoyl-CoA desaturase (SCD)1. In turn, the fatty acid composition of neutral lipids and phospholipids shifts from monounsaturated to saturated fatty acids, and the concentration of the stress-preventive, pro-survival lipokine 1,2-dioleoyl-sn-glycero-3-phospho-(1′-myo-inositol) [PI(18:1/18:1)] decreases. The selective inhibition of SCD1 mimics the pro-apoptotic and anti-proliferative activity of α-T-13′-COOH, and the provision of the SCD1 product oleic acid (C18:1) prevents α-T-13′-COOH-induced apoptosis. We conclude that micromolar concentrations of α-T-13′-COOH trigger cell death and likely also cell cycle arrest by suppressing the SREBP1-SCD1 axis and depleting cells of monounsaturated fatty acids and PI(18:1/18:1).
- Subjects
CELL cycle; STEROL regulatory element-binding proteins; CELL death; MONOUNSATURATED fatty acids; SATURATED fatty acids; LIPIDS; MEMBRANE lipids
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 11, p9229
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms24119229