PDF(Pubmed)
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).
摘要：
α-生育酚-13'-羧基苯并二氢吡喃醇(α-T-13'-COOH)是一种内源性形成的生物活性α-生育酚代谢物，可限制炎症，并已被提议发挥脂质代谢调节作用，促凋亡，和微摩尔浓度下的抗肿瘤特性。这些细胞应激反应的潜在机制是，然而,知之甚少。这里,我们发现,α-T-13\'-COOH引发的巨噬细胞G0/G1细胞周期阻滞和凋亡的诱导与脂质合成代谢转录因子固醇调节元件结合蛋白(SREBP)1的蛋白水解激活抑制和硬脂酰辅酶A去饱和酶(SCD)1的细胞水平降低有关.反过来,中性脂质和磷脂的脂肪酸组成从单不饱和脂肪酸转变为饱和脂肪酸，以及压力预防措施的集中，促存活脂质因子1,2-二油酰基-sn-甘油-3-磷酸-（1'-肌醇）[PI（18：1/18：1）]降低。SCD1的选择性抑制模拟α-T-13\'-COOH的促凋亡和抗增殖活性，并且提供SCD1产物油酸（C18：1）可防止α-T-13\'-COOH诱导的细胞凋亡。我们得出的结论是，微摩尔浓度的α-T-13\'-COOH通过抑制SREBP1-SCD1轴并消耗细胞的单不饱和脂肪酸和PI（18：1/18：1）触发细胞死亡，并可能导致细胞周期停滞。
