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（PUFA）是哺乳动物细胞所有膜的脂质双层中磷脂类的基本结构要素。它们还作为高活性二十烷和二十二烷类化合物的前体发挥作用。ω3-和ω6-PUFAs在脂质代谢的系统稳态中的作用是几十年来深入研究的焦点。西方饮食中ω3-/ω6-PUFAs的比例被认为是脂质稳态遗传调节中的重要表观遗传因素。体内平衡的失衡被认为是慢性代谢性疾病如高脂血症和肥胖症、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。上述几种疾病综合征已被提出作为ω3-PUFAs的治疗靶点，尽管我们对其功能的分子理解缺失。由于ω3-和ω6-PUFAs作为膜和脂蛋白复合物磷脂质替代物的复杂性，以及动物模型和患者群体遗传背景的异质性，导致了数十年来研究结果的不确定性，目前尚无可用于评价ω3-和ω6-PUFAs在系统性内稳态改变的分子研究中的作用的哺乳动物模型。我们通过同源重组产生了一种小鼠模型，其中PUFA合成级联的关键酶Δ6去饱和酶（FADS 2）已被删除。该小鼠突变体在神经元组织中不含ω3-和ω6-PUFA。由于fads 2-/-小鼠是营养缺陷型的，因此它代表了在明确的喂养实验中研究其多效表型的理想系统。我们在严格的喂养实验中，在该遗传上明确定义的小鼠模型中研究了花生四烯酸（ω6-PUFA脂肪酸的主要代表，存在于“陆地食物链”中）和二十二碳六烯酸（ω3-PUFA脂肪酸的主要代表，存在于“海洋食物链”中）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）。阐明fads 2-/-小鼠多效性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明确定义和同质的实验动物中进行。

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.