Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1.
Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1.
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DOI：
10.1038/nm.4059
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发表时间：
2016-04
期刊：
影响因子：
82.9
通讯作者：
Smith LE
中科院分区：
文献类型：
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作者：
Joyal JS;Sun Y;Gantner ML;Shao Z;Evans LP;Saba N;Fredrick T;Burnim S;Kim JS;Patel G;Juan AM;Hurst CG;Hatton CJ;Cui Z;Pierce KA;Bherer P;Aguilar E;Powner MB;Vevis K;Boisvert M;Fu Z;Levy E;Fruttiger M;Packard A;Rezende FA;Maranda B;Sapieha P;Chen J;Friedlander M;Clish CB;Smith LE
高代谢率的组织通常使用脂质和葡萄糖作为能量，在盛宴和饥荒期间赋予生存优势。目前的观点认为，高能量的光感受器依赖于葡萄糖。在这里，我们表明视网膜也使用脂肪酸(FA) β-氧化作为能量。此外，我们确定了一种脂质传感器Ffar1，当FA可用时，它可以抑制葡萄糖的摄取。极低密度脂蛋白受体（VLDLR）在高代谢率组织中表达，促进甘油三酯衍生FA的摄取。Vldlr存在于光感受器中。在Vldlr−/−视网膜中，尽管FA摄取减少，Ffar1仍能感知高循环脂质水平，从而抑制葡萄糖转运蛋白Glut1。这种受损的葡萄糖进入光感受器导致双脂/葡萄糖燃料短缺和克雷布斯循环中间体α-酮戊二酸（KG）的减少。低α-KG水平促进缺氧诱导因子-1α (Hif1a)的稳定和饥饿的Vldlr - / -光受体血管内皮生长因子（Vegfa）的分泌，吸引新生血管提供燃料。这些异常血管侵入Vldlr - / -视网膜中正常无血管的光感受器，使人联想到视网膜血管瘤性增生（RAP），这是新生血管年龄相关性黄斑变性（AMD）的一个亚群，与人类玻璃体中高VEGF水平相关。因此，脂质和葡萄糖光感受器能量代谢失调可能是新生血管性AMD和其他视网膜疾病的驱动力。
Tissues with high metabolic rates often use lipid as well as glucose for energy, conferring a survival advantage during feast and famine. Current dogma suggests that high-energy consuming photoreceptors depend on glucose. Here we show that retina also uses fatty acids (FA) β-oxidation for energy. Moreover, we identify a lipid sensor Ffar1 that curbs glucose uptake when FA are available. Very low-density lipoprotein receptor (VLDLR), expressed in tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived FA. Vldlr is present in photoreceptors. In Vldlr−/− retinas, Ffar1, sensing high circulating lipid levels despite decreased FA uptake, suppresses glucose transporter Glut1. This impaired glucose entry into photoreceptors results in a dual lipid/glucose fuel shortage and reduction in the Krebs cycle intermediate α-ketoglutarate (KG). Low α-KG levels promote hypoxia-induced factor-1α (Hif1a) stabilization and vascular endothelial growth factor (Vegfa) secretion by starved Vldlr−/− photoreceptors, attracting neovessels to supply fuel. These aberrant vessels invading normally avascular photoreceptors in Vldlr−/− retinas are reminiscent of retinal angiomatous proliferation (RAP), a subset of neovascular age-related macular degeneration (AMD), associated with high vitreous VEGF levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in neovascular AMD and other retinal diseases.