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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids
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Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids

机译：Stargardt-3黄斑营养不良蛋白（ELOVL4）在超长链脂肪酸生物合成中的作用

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摘要

Stargardt-like macular dystrophy (STGD3) is a dominantly inherited juvenile macular degeneration that eventually leads to loss of vision. Three independent mutations causing STGD3 have been identified in exon six of a gene named Elongation of very long chain fatty acids 4 (ELOVL4). The ELOVL4 protein was predicted to be involved in fatty acid elongation, although evidence for this and the specific step(s) it may catalyze have remained elusive. Here, using a gain-of-function approach, we provide direct and compelling evidence that ELOVL4 is required for the synthesis of C28 and C30 saturated fatty acids (VLC-FA) and of C28-C38 very long chain polyunsaturated fatty acids (VLC-PUFA), the latter being uniquely expressed in retina, sperm, and brain. Rat neonatal cardiomyocytes and a human retinal epithelium cell line (ARPE-19) were transduced with recombinant adenovirus type 5 carrying mouse Elovl4 and supplemented with 24:0, 20:5n3, or 22:5n3. The 24:0 was elongated to 28:0 and 30:0; 20:Sn3 and 22:5n3 were elongated to a series of C28-C38 PUFA. Because retinal degeneration is the only known phenotype in STGD3 disease, we propose that reduced VLC-PUFA in the retinas of these patients may be the cause of photoreceptor cell death.
机译：像Stargardt样的黄斑营养不良（STGD3）是一种主要遗传的少年性黄斑变性，最终导致视力下降。已经在名为“非常长链脂肪酸4的延伸”（ELOVL4）的基因的第6外显子中鉴定出导致STGD3的三个独立突变。预测ELOVL4蛋白会参与脂肪酸的延伸，尽管对此的证据以及它可能催化的特定步骤仍然难以捉摸。在这里，我们使用功能增益方法提供了直接且令人信服的证据，证明ELOVL4是合成C28和C30饱和脂肪酸（VLC-FA）和C28-C38非常长链多不饱和脂肪酸（VLC- PUFA），后者在视网膜，精子和大脑中独特表达。用携带小鼠Elovl4的5型重组腺病毒转导大鼠新生心肌细胞和人视网膜上皮细胞系（ARPE-19），并补充24：0、20：5n3或22：5n3。 24：0拉长到28：0和30：0； 20：Sn3和22：5n3被延长为一系列C28-C38 PUFA。由于视网膜变性是STGD3疾病中唯一已知的表型，因此我们建议这些患者视网膜中VLC-PUFA的降低可能是感光细胞死亡的原因。

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