The canonical visual cycle employing RPE65 as the retinoid isomerase regenerates 11-cis-retinal to support both rod- and cone-mediated vision. Mutations of RPE65 are associated with Leber congenital amaurosis that results in rod and cone photoreceptor degeneration and vision loss of affected patients at an early age. Dark-reared Rpe65^–/– mouse has been known to form isorhodopsin that employs 9-cis-retinal as the photosensitive chromophore. The mechanism regulating 9-cis-retinal synthesis and the role of the endogenous 9-cis-retinal in cone survival and function remain largely unknown. In this study, we found that ablation of fatty acid transport protein-4 (FATP4), a negative regulator of 11-cis-retinol synthesis catalyzed by RPE65, increased the formation of 9-cis-retinal, but not 11-cis-retinal, in a light-independent mechanism in both sexes of RPE65-null rd12 mice. Both rd12 and rd12;Fatp4^–/– mice contained a massive amount of all-trans-retinyl esters in the eyes, exhibiting comparable scotopic vision and rod degeneration. However, expression levels of M- and S-opsins as well as numbers of M- and S-cones surviving in the superior retinas of rd12;Fatp4^–/– mice were at least twofold greater than those in age-matched rd12 mice. Moreover, FATP4 deficiency significantly shortened photopic b-wave implicit time, improved M-cone visual function, and substantially deaccelerated the progression of cone degeneration in rd12 mice, whereas FATP4 deficiency in mice with wild-type Rpe65 alleles neither induced 9-cis-retinal formation nor influenced cone survival and function. These results identify FATP4 as a new regulator of synthesis of 9-cis-retinal, which is a "cone-tropic" chromophore supporting cone survival and function in the retinas with defective RPE65.

使用 RPE65 作为类视黄醇异构酶的规范视觉循环可再生 11-顺式视黄醛，以支持视杆细胞和视锥细胞介导的视觉。 RPE65 突变与莱伯先天性黑蒙有关，导致患者幼年时视杆细胞和视锥细胞感光细胞退化和视力丧失。已知暗饲养的 Rpe65 ^–/– 小鼠可形成异视紫红质，该异视紫红质采用 9-顺式视黄醛作为光敏发色团。调节 9-顺式视黄醛合成的机制以及内源性 9-顺式视黄醛在视锥细胞存活和功能中的作用仍然很大程度上未知。在这项研究中，我们发现脂肪酸转运蛋白 4 (FATP4)（RPE65 催化的 11-顺式视黄醇合成的负调节因子）的消融增加了 9-顺式视黄醛的形成，但不增加 11-顺式视黄醛的形成，在 RPE65-null rd12 小鼠的两性中存在光独立机制。 rd12 和 rd12;Fatp4 ^–/– 小鼠的眼睛中都含有大量的全反式视黄酯，表现出类似的暗视觉和视杆细胞退化。然而，rd12;Fatp4 ^{–/ –} 小鼠上视网膜中 M- 和 S-视蛋白的表达水平以及存活的 M- 和 S-视锥细胞数量至少是原来的两倍高于年龄匹配的 rd12 小鼠。此外，FATP4 缺乏显着缩短了 rd12 小鼠的明视 b 波隐时时间，改善了 M 视锥细胞视觉功能，并大大减缓了视锥细胞变性的进展，而野生型 Rpe65 等位基因小鼠中的 FATP4 缺乏既不诱导 9-cis-retinal形成也不影响视锥细胞的存活和功能。 这些结果确定 FATP4 是 9-cis-retinal 合成的新调节因子，9-cis-retinal 是一种“视锥细胞性”生色团，支持 RPE65 缺陷的视网膜中视锥细胞的存活和功能。