Janssen Uwe, Stoffel Wilhelm
Laboratory of Molecular Neurosciences, Institute of Biochemistry, Faculty of Medicine, University of Cologne, Joseph-Stelzmannstrasse 52, D-50931 Cologne, Germany.
J Biol Chem. 2002 May 31;277(22):19579-84. doi: 10.1074/jbc.M110993200. Epub 2002 Mar 26.
Cellular energy metabolism is largely sustained by mitochondrial beta-oxidation of saturated and unsaturated fatty acids. To study the role of unsaturated fatty acids in cellular lipid and energy metabolism we generated a null allelic mouse, deficient in 3,2-trans-enoyl-CoA isomerase (ECI) (eci(-/-) mouse). ECI is the link in mitochondrial beta-oxidation of unsaturated and saturated fatty acids and essential for the complete degradation and for maximal energy yield. Mitochondrial beta-oxidation of unsaturated fatty acids is interrupted in eci(-/-)mice at the level of their respective 3-cis- or 3-trans-enoyl-CoA intermediates. Fasting eci(-/-) mice accumulate unsaturated fatty acyl groups in ester lipids and deposit large amounts of triglycerides in hepatocytes (steatosis). Gene expression studies revealed the induction of peroxisome proliferator-activated receptor activation in eci(-/-) mice together with peroxisomal beta- and microsomal omega-oxidation enzymes. Combined peroxisomal beta- and microsomal omega-oxidation of the 3-enoyl-CoA intermediates leads to a specific pattern of medium chain unsaturated dicarboxylic acids excreted in the urine in high concentration (dicarboxylic aciduria). The urinary dicarboxylate pattern is a reliable diagnostic marker of the ECI genetic defect. The eci(-/-) mouse might be a model of a yet undefined inborn mitochondrial beta-oxidation disorder lacking the enzyme link that channels the intermediates of unsaturated fatty acids into the beta-oxidation spiral of saturated fatty acids.
细胞能量代谢在很大程度上由饱和脂肪酸和不饱和脂肪酸的线粒体β-氧化维持。为了研究不饱和脂肪酸在细胞脂质和能量代谢中的作用，我们构建了一种3,2-反式烯酰辅酶A异构酶（ECI）基因敲除的小鼠（eci(-/-)小鼠）。ECI是不饱和脂肪酸和饱和脂肪酸线粒体β-氧化的连接环节，对于完全降解和最大能量产生至关重要。在eci(-/-)小鼠中，不饱和脂肪酸的线粒体β-氧化在各自的3-顺式或3-反式烯酰辅酶A中间体水平被中断。禁食的eci(-/-)小鼠在酯脂质中积累不饱和脂肪酰基，并在肝细胞中沉积大量甘油三酯（脂肪变性）。基因表达研究显示，eci(-/-)小鼠中过氧化物酶体增殖物激活受体被激活，同时过氧化物酶体β-氧化酶和微粒体ω-氧化酶也被诱导。3-烯酰辅酶A中间体的过氧化物酶体β-氧化和微粒体ω-氧化共同作用，导致尿液中以高浓度排泄的中链不饱和二羧酸出现特定模式（二羧酸尿症）。尿液中二羧酸模式是ECI基因缺陷的可靠诊断标志物。eci(-/-)小鼠可能是一种尚未明确的先天性线粒体β-氧化障碍模型，缺乏将不饱和脂肪酸中间体导入饱和脂肪酸β-氧化螺旋的酶连接环节。
