Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg Germany.
J Lipid Res. 2010 Jan;51(1):182-91. doi: 10.1194/jlr.M900289-JLR200.
Fatty acid desaturases (FADS) play an important role in the formation of omega-6 and omega-3 highly unsaturated fatty acids (HUFAs). The composition of HUFAs in the human metabolome is important for membrane fluidity and for the modulation of essential physiological functions such as inflammation processes and brain development. Several recent studies reported significant associations of single nucleotide polymorphisms (SNPs) in the human FADS gene cluster with HUFA levels and composition. The presence of the minor allele correlated with a decrease of desaturase reaction products and an accumulation of substrates. We performed functional studies with two of the associated polymorphisms (rs3834458 and rs968567) and showed an influence of polymorphism rs968567 on FADS2 promoter activity by luciferase reporter gene assays. Electrophoretic mobility shift assays proved allele-dependent DNA-binding ability of at least two protein complexes to the region containing SNP rs968567. One of the proteins binding to this region in an allele-specific manner was shown to be the transcription factor ELK1 (a member of ETS domain transcription factor family). These results indicate that rs968567 influences FADS2 transcription and offer first insights into the modulation of complex regulation mechanisms of FADS2 gene transcription by SNPs.
脂肪酸去饱和酶（FADS）在形成ω-6 和 ω-3 高度不饱和脂肪酸（HUFAs）方面发挥着重要作用。人类代谢组中 HUFAs 的组成对于膜流动性以及炎症过程和大脑发育等基本生理功能的调节非常重要。最近的几项研究报告称，人类 FADS 基因簇中的单核苷酸多态性（SNP）与 HUFAs 水平和组成存在显著关联。次要等位基因的存在与去饱和酶反应产物的减少和底物的积累相关。我们对两个相关的多态性（rs3834458 和 rs968567）进行了功能研究，并通过荧光素酶报告基因检测显示多态性 rs968567 对 FADS2 启动子活性的影响。电泳迁移率变动分析证明了至少两种蛋白复合物对包含 SNP rs968567 的区域具有依赖于等位基因的 DNA 结合能力。以等位基因特异性方式结合到该区域的一种蛋白质被证明是转录因子 ELK1（ETS 结构域转录因子家族的成员）。这些结果表明 rs968567 影响 FADS2 转录，并为 SNP 对 FADS2 基因转录的复杂调控机制的调节提供了初步见解。
