Conversion of all-trans-retinal into all-trans-retinal dimer reflects an alternative metabolic/antidotal pathway of all-trans-retinal in the retina
Conversion of all-trans-retinal into all-trans-retinal dimer reflects an alternative metabolic/antidotal pathway of all-trans-retinal in the retina
复制标题
全反式视网膜向全反式视网膜二聚体的转化反映了视网膜中全反式视网膜的替代代谢/解毒途径
DOI：
10.1074/jbc.ra118.002447
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发表时间：
2018-09-14
影响因子：
4.8
通讯作者：
Wu, Yalin
中科院分区：
文献类型：
--
作者：
Gao, Zhan;Liao, Yi;Wu, Yalin
游离全反式视网膜（atRAL）和视网膜色素上皮（RPE）脂褐素都被认为在Stargardt病和年龄相关性黄斑变性中起病因作用。A2 E和全反式-视网膜二聚体（atRAL-二聚体）是RPE脂褐质的两种充分表征的双维甲酸成分。在这项研究中，我们发现，原代猪RPE（pRPE）细胞与atRAL处理后，atRAL-二聚体很容易形成和积累的浓度和时间依赖性的方式，但A2 E几乎没有检测到。基于细胞的测定显示，atRAL，atRAL-二聚体的前体，在80 μm的浓度下显著改变原代pRPE细胞的形态，并降低细胞活力，而与光暴露无关。相比之下，atRAL-二聚体对原代pRPE细胞没有细胞毒性和光毒性。与atRAL和A2 E相比，atRAL-二聚体更易受光损伤，产生光裂解产物。此外，我们观察到atRAL-二聚体的存在下，atRAL与猪杆外段（ROS），RPE/脉络膜，或神经视网膜的反应混合物。综上所述，我们在此提出了atRAL在视网膜中的替代代谢/解毒途径：逃避视觉（类视色素）循环参与的atRAL经历缩合反应，在ROS和RPE中产生atRAL-二聚体。atRAL、全反式N-亚视黄基-磷脂酰乙醇胺（NR-PE）、atRAL-二聚体和atRAL-二聚体的光裂解产物从ROS到RPE的转运通过每天吞噬脱落的ROS来完成。在不对RPE细胞造成损伤的情况下，光分解RPE细胞内的总atRAL-二聚体以释放低分子量的光裂解片段。后者与ROS-atRAL-二聚体光裂解产物一起可以容易地穿过膜，从而被代谢消除。
Free all-trans-retinal (atRAL) and retinal pigment epithelium (RPE) lipofuscin are both considered to play etiological roles in Stargardt disease and age-related macular degeneration. A2E and all-trans-retinal dimer (atRAL-dimer) are two well characterized bisretinoid constituents of RPE lipofuscin. In this study, we found that, after treatment of primary porcine RPE (pRPE) cells with atRAL, atRAL-dimer readily formed and accumulated in a concentration- and time-dependent manner, but A2E was barely detected. Cell-based assays revealed that atRAL, the precursor of atRAL-dimer, significantly altered the morphology of primary pRPE cells and decreased cell viability at a concentration of 80 μm regardless of light exposure. By contrast, atRAL-dimer was not cytotoxic and phototoxic to primary pRPE cells. Compared with atRAL and A2E, atRAL-dimer was more vulnerable to light, followed by the generation of its photocleaved products. Moreover, we observed the presence of atRAL-dimer in reaction mixtures of atRAL with porcine rod outer segments (ROS), RPE/choroid, or neural retina. Taken together, we here proposed an alternative metabolic/antidotal pathway of atRAL in the retina: atRAL that evades participation of the visual (retinoid) cycle undergoes a condensation reaction to yield atRAL-dimer in both ROS and RPE. Translocation of atRAL, all-trans N-retinylidene–phosphatidylethanolamine (NR-PE), atRAL-dimer, and photocleavage products of atRAL-dimer from ROS into RPE is accomplished by phagocytosing shed ROS on a daily basis. Without causing damage to RPE cells, light breaks up total atRAL-dimer within RPE cells to release low-molecular-weight photocleavage fragments. The latter, together with ROS-atRAL-dimer photocleavage products, may easily move across membranes and thereby be metabolically eliminated.