Δ6-脂肪酸去饱和酶（FADS2）缺乏导致肥胖抵抗和脂生成失调。
Obesity resistance and deregulation of lipogenesis in Δ6-fatty acid desaturase (FADS2) deficiency.
机构信息
Center of Molecular Medicine (CMMC) Laboratory of Molecular Neurosciences, Institute of Biochemistry University of Cologne, Cologne, Germany.
出版信息
EMBO Rep. 2014 Jan;15(1):110-20. doi: 10.1002/embr.201338041. Epub 2013 Dec 30.
Abstract
Δ-6-fatty acid desaturase (FADS2) is the key enzyme in the biosynthesis of polyunsaturated fatty acids (PUFAs), the essential structural determinants of mammalian membrane lipid-bilayers. We developed the auxotrophic fads2(-/-) mouse mutant to assess the enigmatic role of ω3- and ω6-PUFAs in lipid homeostasis, membrane structure and function. Obesity resistance is another major phenotype of the fads2(-/-) mutant, the molecular basis of which is unknown. Phospholipidomic profiling of membrane systems of fads2(-/-)mice revealed diacylglycerol-structures, deprived of PUFAs but substituted with surrogate eicosa-5,11,14-trienoic acid. ω6-Arachidonic (AA) and ω3-docosahexaenoic acid (DHA) supplemented diets transformed fads2(-/-) into AA-fads2(-/-) and DHA-fads2(-/-) mutants. Severely altered phospholipid-bilayer structures of subcellular membranes of fads2(-/-) liver specifically interfered with maturation of transcription factor sterol-regulatory-element-binding protein, the key regulator of lipogenesis and lipid homeostasis. This study strengthens the concept that specific PUFA-substituted membrane phospholipid species are critical constituents of the structural platform operative in lipid homeostasis in normal and disease conditions.
摘要
Δ-6-脂肪酸去饱和酶（FADS2）是多不饱和脂肪酸（PUFA）生物合成的关键酶，是哺乳动物膜脂双层的必需结构决定因素。我们开发了必需基因敲除型（fads2(-/-)）小鼠突变体，以评估ω3 和 ω6-PUFA 在脂质稳态、膜结构和功能中的神秘作用。肥胖抵抗是 fads2(-/-)突变体的另一个主要表型，其分子基础尚不清楚。膜系统磷脂组学分析显示，二酰基甘油结构缺乏多不饱和脂肪酸，但被替代的二十碳五烯酸取代。ω6-花生四烯酸（AA）和 ω3-二十二碳六烯酸（DHA）补充饮食将 fads2(-/-)转化为 AA-fads2(-/-)和 DHA-fads2(-/-)突变体。fads2(-/-)肝脏亚细胞膜的严重改变的磷脂双层结构特别干扰了转录因子固醇调节元件结合蛋白的成熟，该蛋白是脂生成和脂质稳态的关键调节剂。本研究加强了这样一种概念，即特定的 PUFA 取代的膜磷脂种类是正常和疾病条件下脂质稳态结构平台的关键组成部分。
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