α-Tocopherol-13'-Carboxychromanol Induces Cell Cycle Arrest and Cell Death by Inhibiting the SREBP1-SCD1 Axis and Causing Imbalance in Lipid Desaturation.
Int J Mol Sci
; 24(11)2023 May 25.
Article
em En
| MEDLINE
| ID: mdl-37298183
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(181/181)] 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 (C181) 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(181/181).
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tocoferóis
/
Alfa-Tocoferol
Idioma:
En
Revista:
Int J Mol Sci
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Alemanha