Essential Role of ELOVL4 Protein in Very Long Chain Fatty Acid Synthesis and Retinal Function
Essential Role of ELOVL4 Protein in Very Long Chain Fatty Acid Synthesis and Retinal Function
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DOI：
10.1074/jbc.m111.256073
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发表时间：
2012-03-30
影响因子：
4.8
通讯作者：
Zhang, Kang
中科院分区：
文献类型：
--
作者：
Harkewicz, Richard;Du, Hongjun;Zhang, Kang
含有甚长链多不饱和脂肪酸（VLC-PUFA）的甘油磷脂在视网膜中高度富集；然而，关于这些非常不寻常的视网膜甘油磷脂的具体合成和功能的细节是缺乏的。超长链脂肪酸延伸-4 （ELOVL4）是一种参与VLC-PUFAs合成的脂肪酸延伸酶蛋白。ELOVL4的突变也与Stargardt病（STGD3）的常染色体显性形式有关，STGD3是一种青少年黄斑变性。我们培育了光感受器特异性条件敲除小鼠，并使用高效液相色谱-质谱（HPLC-MS）检测和分析了视网膜膜中甘油磷脂酰胆碱和甘油磷脂酰乙醇胺的脂肪酸组成。我们还使用免疫荧光染色和组织学结合电生理数据来评估视网膜形态和视觉反应。条件敲除小鼠显示含有VLC-PUFAs的视网膜甘油磷脂显著减少，特别是含有在甘油磷脂酰胆碱的sn-1位置，暗示Elovl4在其合成中的作用。条件敲除小鼠还发现脂滴和脂褐素样颗粒的异常积聚，同时在视觉反应中表现出光感受器特异性异常，表明Elovl4在正常的杆状或锥状光感受器功能中起关键作用。综上所述，本研究证明了ELOVL4在VLCPUFA合成和视网膜功能中的重要作用。
Very long chain polyunsaturated fatty acid (VLC-PUFA)-containing glycerophospholipids are highly enriched in the retina; however, details regarding the specific synthesis and function of these highly unusual retinal glycerophospholipids are lacking. Elongation of very long chain fatty acids-4 (ELOVL4) has been identified as a fatty acid elongase protein involved in the synthesis of VLC-PUFAs. Mutations in ELOVL4 have also been implicated in an autosomal dominant form of Stargardt disease (STGD3), a type of juvenile macular degeneration. We have generated photoreceptor-specific conditional knock-out mice and used high performance liquid chromatography-massspectrometry (HPLC-MS) to examine and analyze the fatty acid composition of retinal membrane glycerophosphatidylcholine and glycerophosphatidylethanolamine species. We also used immunofluorescent staining and histology coupled with electrophysiological data to assess retinal morphology and visual response. The conditional knock-out mice showed a significant decrease in retinal glycerophospholipids containing VLC-PUFAs, specifically contained in the sn-1 position of glycerophosphatidylcholine, implicating the role of Elovl4 in their synthesis. Conditional knock-out mice were also found to have abnormal accumulation of lipid droplets and lipofuscin-like granules while demonstrating photoreceptor-specific abnormalities in visual response, indicating the critical role of Elovl4 for proper rod or cone photoreceptor function. Altogether, this study demonstrates the essential role of ELOVL4 in VLCPUFA synthesis and retinal function.