α-Tocopherol-13′-Carboxychromanol Induces Cell Cycle Arrest and Cell Death by Inhibiting the SREBP1-SCD1 Axis and Causing Imbalance in Lipid Desaturation

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).

Chemopreventive effects of α-tocopherol and its long-chain metabolites α-13′-hydroxy- and α-13′-carboxychromanol in LT97 colon adenoma cells

“…In the present study, cyclin D2 was analyzed and a marginal but insignificant decline in mRNA levels was observed, whereas p21 mRNA levels were not affected. In a recent study, Liao et al 47 demonstrated that α-13′-COOH modulated the cell cycle and insignificantly upregulated p21 gene expression in murine macrophages. Treatment of murine RAW264.7 macrophages with α-13′-COOH resulted in an induction of G0/G1 cell cycle arrest and apoptosis which was associated with a suppressed proteolytic activation of the sterol regulatory element-binding protein (SREBP)1 and with decreased cellular levels of stearoyl-CoA desaturase 1 (SCD1).…”