Effects of n-3 polyunsaturated fatty acids and their derivatives on gene expression and cytokine production.

脂肪酸传统上被认为是几种生物体中参与能量和底物通量的中间代谢物。然而，现在已经非常清楚，细胞和组织脂肪酸含量的增加可以通过多种机制影响细胞功能，包括膜物理性质的改变以及细胞信号传导途径和基因表达的调节。例如，我们和其他人已经观察到，使用鱼油胶囊补充omega-3或n-3多不饱和脂肪酸（n3-PUFA）可以显著改变人类血液单核细胞的基因表达谱。在对富含二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）的油性鱼或鱼油进行的人类干预研究中，一直报告了n-3 PUFA的有益健康作用。这些作用主要归因于：1）n-3 PUFA修饰转录因子表达的能力;和2）脂质介质（包括消退素和保护素）的改变。然而，人体试验有几个限制。首先，研究EPA、DHA及其脂质介质对基因表达的独立影响相对困难。人体试验的另一个限制是靶组织的获取。在目前的研究计划中，我们希望开发细胞培养模型，用于进行体外研究，解决n-3 PUFA及其衍生物对细胞和分子的影响。将使用基因表达谱或转录组学来观察n-3 PUFA及其脂质介质对已知调节胆固醇稳态和炎症介质的基因的独立影响。此外，将研究n-3 PUFA及其脂质介质抑制炎性细胞因子产生的潜力。这种综合的方法将有助于阐明的潜在机制，解释细胞和分子的变化归因于n-3 PUFA和铺平道路的生物活性脂质的生物学效应的研究。此外，它将有助于在不断发展的营养基因组学领域培养高素质的人才。

Fatty acids were traditionally thought to represent intermediary metabolites involved in energy and substrate fluxes in several living organisms. However, it has now become very clear that increased cell and tissue fatty acid content can influence cell function through a variety of mechanisms including alterations in the physical property of the membrane as well as modulation of cell signalling pathways and gene expression. For example, we and others have observed that omega-3 or n-3 polyunsaturated fatty acid (n3-PUFA) supplementation using fish oil capsules substantially alters the gene expression profile of blood mononuclear cells in humans. Beneficial health effects of n-3 PUFAs have been consistently reported in human intervention studies with oily fish or fish oil that are rich in eicosapentanoic acid (EPA) and decohexaenoic acid (DHA). The effects are mainly attributable: 1) to the ability of n-3 PUFAs to modify the expression of transcription factors; and 2) to alterations in lipid mediators including resolvins and protectins. However, there are several limitations to human trials. First, it is relatively difficult to study the independent effect of EPA, DHA and their lipid mediators on gene expression. Another limitation of human trials is the access to target tissues. In the present research program, we want to develop cell culture models that will be used to perform in vitro studies addressing the cellular and molecular impact of n-3 PUFAs and their derivatives. Gene expression profiling or transcriptomics will be used in order to look at the independent effects of n-3 PUFAs and their lipid mediators on genes known to regulate cholesterol homeostasis and inflammatory mediators. In addition, the potential of n-3 PUFAs and their lipid-mediators to suppress inflammatory cytokine production will be studied. Such an integrated approach will help elucidate the underlying mechanisms explaining cellular and molecular changes attributable to n-3 PUFAs and pave the way for studies on the biological effects of bioactive lipids. Also, it will contribute to the training of highly qualified personnals in the growing field of nutrigenomics.