Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH.
F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
J Lipid Res. 2018 Dec;59(12):2368-2382. doi: 10.1194/jlr.M090043. Epub 2018 Oct 17.
Apolipoprotein E (APOE) is a component of lipid-transporting particles and a recognition ligand for receptors, which bind these particles. The APOE isoform ε2 is a risk factor for age-related macular degeneration; nevertheless, APOE absence in humans and mice does not significantly affect the retina. We found that retinal cholesterol biosynthesis and the levels of retinal cholesterol were increased in mice, whereas cholesterol elimination by metabolism was decreased. No focal cholesterol deposits were observed in the retina. Retinal proteomics identified the most abundant cholesterol-related proteins in WT mice and revealed that, of these cholesterol-related proteins, only APOA4 had increased expression in the retina. In addition, there were changes in retinal abundance of proteins involved in proinflammatory and antiinflammatory responses, cellular cytoskeleton maintenance, vesicular traffic, and retinal iron homeostasis. The data obtained indicate that when APOE is absent, particles containing APOA1, APOA4, and APOJ still transport cholesterol in the intraretinal space, but these particles are not taken up by retinal cells. Therefore, cholesterol biosynthesis inside retinal cells increase, whereas metabolism to oxysterols decreases to prevent cells from cholesterol depletion. These and other compensatory changes underlie only a minor retinal phenotype in mice.
载脂蛋白 E (APOE) 是脂质转运颗粒的组成部分，也是与这些颗粒结合的受体的识别配体。APOE 同种型 ε2 是与年龄相关的黄斑变性的危险因素；然而，人类和小鼠中 APOE 的缺失并不会显著影响视网膜。我们发现， 小鼠的视网膜胆固醇生物合成和视网膜胆固醇水平增加，而胆固醇通过代谢消除减少。在 视网膜中未观察到焦点胆固醇沉积。视网膜蛋白质组学鉴定了 WT 小鼠中最丰富的与胆固醇相关的蛋白质，并表明，在这些与胆固醇相关的蛋白质中，只有 APOA4 在 视网膜中的表达增加。此外，参与促炎和抗炎反应、细胞细胞骨架维持、囊泡运输和视网膜铁稳态的蛋白质在视网膜中的丰度也发生了变化。获得的数据表明，当 APOE 缺失时，含有 APOA1、APOA4 和 APOJ 的颗粒仍在视网膜内空间转运胆固醇，但这些颗粒不会被视网膜细胞摄取。因此，视网膜细胞内的胆固醇生物合成增加，而代谢为氧化固醇减少，以防止细胞胆固醇耗竭。这些和其他代偿性变化仅导致 小鼠的视网膜表型轻微。
