Joyal Jean-Sébastien, Sun Ye, Gantner Marin L, Shao Zhuo, Evans Lucy P, Saba Nicholas, Fredrick Thomas, Burnim Samuel, Kim Jin Sung, Patel Gauri, Juan Aimee M, Hurst Christian G, Hatton Colman J, Cui Zhenghao, Pierce Kerry A, Bherer Patrick, Aguilar Edith, Powner Michael B, Vevis Kristis, Boisvert Michel, Fu Zhongjie, Levy Emile, Fruttiger Marcus, Packard Alan, Rezende Flavio A, Maranda Bruno, Sapieha Przemyslaw, Chen Jing, Friedlander Martin, Clish Clary B, Smith Lois E H
Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montreal, Quebec, Canada.
Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada.
Nat Med. 2016 Apr;22(4):439-45. doi: 10.1038/nm.4059. Epub 2016 Mar 14.
Tissues with high metabolic rates often use lipids, 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 the retina also uses fatty acid β-oxidation for energy. Moreover, we identify a lipid sensor, free fatty acid receptor 1 (Ffar1), that curbs glucose uptake when fatty acids are available. Very-low-density lipoprotein receptor (Vldlr), which is present in photoreceptors and is expressed in other tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acid. In the retinas of Vldlr(-/-) mice with low fatty acid uptake but high circulating lipid levels, we found that Ffar1 suppresses expression of the glucose transporter Glut1. Impaired glucose entry into photoreceptors results in a dual (lipid and glucose) fuel shortage and a reduction in the levels of the Krebs cycle intermediate α-ketoglutarate (α-KG). Low α-KG levels promotes stabilization of hypoxia-induced factor 1a (Hif1a) and secretion of vascular endothelial growth factor A (Vegfa) by starved Vldlr(-/-) photoreceptors, leading to neovascularization. The aberrant vessels in the Vldlr(-/-) retinas, which invade normally avascular photoreceptors, are reminiscent of the vascular defects in retinal angiomatous proliferation, a subset of neovascular age-related macular degeneration (AMD), which is associated with high vitreous VEGFA levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in macular telangiectasia, neovascular AMD and other retinal diseases.
代谢率高的组织通常利用脂质以及葡萄糖来获取能量，这使其在饱食和饥饿期间都具有生存优势。当前的理论认为，高耗能的光感受器依赖葡萄糖。在此我们表明，视网膜也利用脂肪酸β-氧化来获取能量。此外，我们鉴定出一种脂质传感器——游离脂肪酸受体1（Ffar1），当有脂肪酸可用时，它会抑制葡萄糖摄取。极低密度脂蛋白受体（Vldlr）存在于光感受器中，并在其他代谢率高的组织中表达，它有助于摄取甘油三酯衍生的脂肪酸。在脂肪酸摄取量低但循环脂质水平高的Vldlr基因敲除小鼠的视网膜中，我们发现Ffar1会抑制葡萄糖转运蛋白Glut1的表达。葡萄糖进入光感受器受损会导致脂质和葡萄糖双重燃料短缺，以及三羧酸循环中间产物α-酮戊二酸（α-KG）水平降低。低α-KG水平会促进缺氧诱导因子1a（Hif1a）的稳定，并促使饥饿的Vldlr基因敲除光感受器分泌血管内皮生长因子A（Vegfa），从而导致新生血管形成。Vldlr基因敲除小鼠视网膜中的异常血管侵入正常无血管的光感受器，这让人联想到视网膜血管瘤样增殖中的血管缺陷，后者是新生血管性年龄相关性黄斑变性（AMD）的一个子集，与人类玻璃体中高VEGFA水平有关。因此，脂质和葡萄糖光感受器能量代谢失调可能是黄斑毛细血管扩张、新生血管性AMD和其他视网膜疾病的驱动因素。
