Unravelling the systemic functions of omega3- and omega6-polyunsaturated fatty acids in genetically defined delta6-fatty acid desaturase (fads2-/-) deficient mouse mutants

ω3-和ω6 -多烯脂肪酸（PUFAs）是哺乳动物细胞膜脂质双分子层中磷脂类必不可少的结构元素。它们也作为药理学上高度活跃的双星和二十二烷的前体发挥作用。ω3-和ω6-PUFAs在脂质代谢系统稳态中的作用是几十年来研究的重点。西方饮食中ω3-/ω6-PUFAs的比例被认为是脂质稳态遗传调控的重要表观遗传因子。体内平衡失衡被认为是慢性代谢性疾病如高甘油三酯血症和肥胖、脂肪肝、2型糖尿病、心血管疾病、胰岛素抵抗和炎症，甚至神经退行性疾病和精神疾病发展的驱动机制。我们目前的大量饲养实验和流行病学研究的知识库解决了ω3-和ω6- pufa的作用。尽管我们对ω3-PUFAs功能的分子理解尚不清楚，但上述几种疾病综合征已被提出作为ω3-PUFAs的治疗靶点。几十年来积累的结果不明确的原因是ω3-和ω6- pufa作为膜和脂蛋白复合物磷脂的替代品的复杂性，动物模型和患者群体遗传背景的异质性。到目前为止，还没有哺乳动物模型来评估ω3-和ω6-PUFAs在系统性体内平衡改变的分子研究中的作用。通过同源重组，我们建立了一个小鼠模型，其中PUFA合成级联的关键酶Δ6去饱和酶（FADS2）被删除。该小鼠突变体在神经元外组织中不含ω3-和ω6-PUFAs。由于fads2-/-小鼠是一种营养不良小鼠，因此它是研究其多效性表型的理想系统。在严格的饲养实验中，我们研究了“陆地食物链”中ω6-PUFA脂肪酸的主要代表花生四烯酸和“海洋食物链”中ω3- pufa脂肪酸的主要代表二十二碳己酸的作用，以及两种必需脂肪酸ω3-α-亚麻酸-(18:3)和ω6-亚油酸（18:2）的作用。阐明fads2-/-小鼠多效表型复杂性的机制和分子研究现在可以在有限数量的遗传上定义良好的同质实验动物中进行。

ω3- and ω6–polyenoic fatty acids (PUFAs) are essential structural elements of phospholipid classes in the lipid bilayer of all membranes of mammalian cells. They also function as precursors of pharmacologically highly active eicosa- and docosanoids. The role of ω3- and ω6–PUFAs in systemic homeostasis of lipid metabolism is in the focus of intensive research of many decades. The ratio of ω3-/ω6-PUFAs in western diet is regarded as essential epigenetic factor in the genetic regulation of lipid homeostasis. Imbalances of homeostasis are postulated as driving mechanism in the development of chronic metabolic diseases like hypertriglyceridemia and obesitas, fatty liver, type-2-diabetes, cardiovascular diseases, insulin resistance and inflammation and even neurodegenerative and psychiatric disease.Our present knowledge bases of numerous feeding experiments and epidemiological studies adresses the role of ω3- and ω6-PUFAs. Several of the disease syndroms, mentioned above, have been proposed as therapeutical targets for ω3-PUFAs altough our molecular understanding of their function is missing. The reasons of the ambiguity of results accumulated over decades is the complexity of the ω3- and ω6-PUFAs as substitutes in the phospholipidom of membranes and lipoprotein complexes, the heterogenity of the genetic background of animal models and patient collectives.So far no mammalian animal model was available to assess the role of ω3- and ω6-PUFAs in molecular studies of the systemic altered homeostasis. We have generated, by homologous recombination, a mouse model in which the key enzyme of the PUFA synthesis cascade, the Δ6 desaturase (FADS2), has been deleted. This mouse mutant is free of ω3- and ω6-PUFAs in extraneuronal tissue. Since the fads2-/- mouse is auxotrophic, it represents an ideal system to study it's pleitropic phenotype in unambiguous feeding experiments. We study in this genetically well definded mouse model in stringent feeding experiments the role of arachidonic acid, the main representative of the ω6-PUFA fatty acids, occuring in the "land food chain" and of docosahexanoic acid, the main representative of the ω3-PUFA fatty acids, occuring in the "sea food chain", as well as the role of the two essentiell fatty acids ω3-α-linolenic- (18:3) and ω6-linoleic-acid (18:2). Mechanistic and molecular studies elucidating the complexity of the pleiotropic phenotype in the fads2-/- mice can now be adressed in a limited number of genetically well defined and homogeneous experimental animals.