Mutations in the adiponectin receptor 1 gene () lead to retinitis pigmentosa and are associated with age-related macular degeneration. This study explores the effects of AdipoR1 gene deficiency in mice, revealing a striking decline in ω3 polyunsaturated fatty acids (PUFA), an increase in ω6 fatty acids, and elevated ceramides in the retina. The AdipoR1 deficiency impairs peroxisome proliferator-activated receptor α signaling, which is crucial for FA metabolism, particularly affecting proteins associated with FA transport and oxidation in the retina and retinal pigmented epithelium. Our lipidomic and proteomic analyses indicate changes that could affect membrane composition and viscosity through altered ω3 PUFA transport and synthesis, suggesting a potential influence of AdipoR1 on these properties. Furthermore, we noted a reduction in the Bardet-Biedl syndrome proteins, which are crucial for forming and maintaining photoreceptor outer segments that are PUFA-enriched ciliary structures. Diminution in Bardet-Biedl syndrome-proteins content combined with our electron microscopic observations raises the possibility that AdipoR1 deficiency might impair ciliary function. Treatment with inhibitors of ceramide synthesis led to substantial elevation of ω3 LC-PUFAs, alleviating photoreceptor degeneration and improving retinal function. These results serve as the proof of concept for a ceramide-targeted strategy to treat retinopathies linked to PUFA deficiency, including age-related macular degeneration.

中文翻译：

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通过靶向神经酰胺恢复 AdipoR1 缺陷小鼠的视网膜多不饱和脂肪酸平衡和视网膜功能


脂联素受体 1 基因 () 的突变会导致色素性视网膜炎，并与年龄相关性黄斑变性相关。这项研究探讨了 AdipoR1 基因缺陷对小鼠的影响，揭示了视网膜中 ω3 多不饱和脂肪酸 (PUFA) 的显着下降、ω6 脂肪酸的增加以及神经酰胺的升高。 AdipoR1 缺陷会损害过氧化物酶体增殖物激活受体 α 信号传导，这对于 FA 代谢至关重要，特别是影响与视网膜和视网膜色素上皮中 FA 运输和氧化相关的蛋白质。我们的脂质组学和蛋白质组学分析表明，通过改变 ω3 PUFA 转运和合成，可能会影响膜组成和粘度，表明 AdipoR1 对这些特性的潜在影响。此外，我们注意到 Bardet-Biedl 综合征蛋白的减少，这些蛋白对于形成和维持富含 PUFA 的睫状结构的光感受器外节至关重要。 Bardet-Biedl 综合征蛋白质含量的减少与我们的电子显微镜观察相结合，提出了 AdipoR1 缺乏可能损害纤毛功能的可能性。使用神经酰胺合成抑制剂治疗可显着提高 ω3 LC-PUFA，从而减轻感光器变性并改善视网膜功能。这些结果作为神经酰胺靶向策略的概念证明，用于治疗与 PUFA 缺乏相关的视网膜病，包括年龄相关性黄斑变性。