5-Lipoxygenase as immunoregulatory target of human endogenous vitamin E metabolites

维生素E具有免疫调节功能，在低剂量下可预防代谢和炎症性疾病。长期以来，这种维生素一直被视为纯粹的抗氧化剂。与此同时，基础研究的重点转移到了非氧化还原机制上，并假设维生素E会转化为生物活性代谢物，就像其他脂溶维生素一样。我们的数据表明，维生素E的代谢产物13‘-羧基-α-生育酚是在体内内源性形成的，并通过抑制5-脂氧合酶而参与维生素E的抗炎特性--5-脂氧合酶是免疫调节脂质介体生物合成的关键酶。在本方案中，我们将详细研究维生素E代谢物的结合模式和抑制机制，并表征13‘-羧基-α-生育酚作为内源性代谢物在人的初级免疫细胞、基于生物芯片的微灌流三维肝脏器官以及在小鼠炎症模型中的特征。我们的结果将为维生素E的复杂机制提供洞察力，并可能对维生素E补充剂研究的设计和解释具有重要意义。

Vitamin E has immunoregulatory functions and protects from metabolic and inflammatory diseases at low dosage. The vitamin has long been viewed as mere antioxidant. Meanwhile, the focus of basic research shifted to non-redox mechanisms, and it has been hypothesized that vitamin E is converted into bioactive metabolites, as known for other fat-soluble vitamins. Our data indicate that the vitamin E metabolite 13'-carboxy-alpha-tocopherol is endogenously formed in the body and contributes to the anti-inflammatory properties of vitamin E through inhibition of 5-lipoxygenase - a key enzyme in the biosynthesis of immunoregulatory lipid mediators. In the present proposal, we will in detail investigate the binding mode and inhibitory mechanism of vitamin E metabolites and characterize 13'-carboxy-alpha-tocopherol as endogenous metabolite in human primary immune cells, in a biochip-based microperfused three-dimensional liver organoid as well as in a mouse model of inflammation. Our results will provide insights into the complex mechanisms of vitamin E and might be of major importance for the design and interpretation of vitamin E supplementation studies.