The marine n-3 PUFA DHA evokes cytoprotection against oxidative stress and protein misfolding by inducing autophagy and NFE2L2 in human retinal pigment epithelial cells.
The marine n-3 PUFA DHA evokes cytoprotection against oxidative stress and protein misfolding by inducing autophagy and NFE2L2 in human retinal pigment epithelial cells.
复制标题
DOI：
10.1080/15548627.2015.1061170
复制
发表时间：
2015
期刊：
影响因子：
13.3
通讯作者：
Bjørkøy G
中科院分区：
文献类型：
--
作者：
Johansson I;Monsen VT;Pettersen K;Mildenberger J;Misund K;Kaarniranta K;Schønberg S;Bjørkøy G
错误折叠蛋白质的积累和聚集是几种统称为蛋白质病的疾病的一个标志。自噬在与蛋白质聚集体相关的疾病中具有细胞保护作用。年龄相关性黄斑变性（AMD）是导致老年人失明的最常见的神经退行性眼病。AMD的特征是视网膜色素上皮（RPE）细胞变性，并导致光感受器细胞和中心视力丧失。初始阶段与细胞内脂褐素的积累以及称为玻璃膜疣的细胞外沉积物有关。流行病学研究表明，海洋n - 3多不饱和脂肪酸（PUFAs）的膳食摄入量与包括AMD在内的神经退行性疾病的发病风险呈负相关。然而，n - 3 PUFAs所启动的疾病预防机制尚未完全清楚。在人视网膜色素上皮细胞中，我们发现生理相关剂量的n - 3多不饱和脂肪酸二十二碳六烯酸（DHA）会诱导细胞内活性氧（ROS）水平短暂升高，从而激活氧化应激反应调节因子NFE2L2/NRF2（核因子，红系衍生2，样2）。同时，含有SQSTM1/p62（隔离蛋白1）的细胞内蛋白质聚集体短暂增加，自噬也增加。用DHA预处理可使细胞从错误折叠蛋白质或氧化应激诱导的细胞周期停滞中恢复。氧化应激反应或自噬下调的细胞在补充DHA后细胞生长和存活减少。这些结果表明，DHA既能诱导内源性抗氧化剂，又能启动对错误折叠蛋白质的选择性自噬。这两种机制都可能与降低发生诸如AMD等与聚集体相关疾病的风险有关。
Accumulation and aggregation of misfolded proteins is a hallmark of several diseases collectively known as proteinopathies. Autophagy has a cytoprotective role in diseases associated with protein aggregates. Age-related macular degeneration (AMD) is the most common neurodegenerative eye disease that evokes blindness in elderly. AMD is characterized by degeneration of retinal pigment epithelial (RPE) cells and leads to loss of photoreceptor cells and central vision. The initial phase associates with accumulation of intracellular lipofuscin and extracellular deposits called drusen. Epidemiological studies have suggested an inverse correlation between dietary intake of marine n-3 polyunsaturated fatty acids (PUFAs) and the risk of developing neurodegenerative diseases, including AMD. However, the disease-preventive mechanism(s) mobilized by n-3 PUFAs is not completely understood. In human retinal pigment epithelial cells we find that physiologically relevant doses of the n-3 PUFA docosahexaenoic acid (DHA) induce a transient increase in cellular reactive oxygen species (ROS) levels that activates the oxidative stress response regulator NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2). Simultaneously, there is a transient increase in intracellular protein aggregates containing SQSTM1/p62 (sequestosome 1) and an increase in autophagy. Pretreatment with DHA rescues the cells from cell cycle arrest induced by misfolded proteins or oxidative stress. Cells with a downregulated oxidative stress response, or autophagy, respond with reduced cell growth and survival after DHA supplementation. These results suggest that DHA both induces endogenous antioxidants and mobilizes selective autophagy of misfolded proteins. Both mechanisms could be relevant to reduce the risk of developing aggregate-associate diseases such as AMD.