Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1

作者：Joyal Jean Sebastien^*; 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

来源：Nature Medicine, 2016, 22(4): 439-+.

DOI：10.1038/nm.4059

Tissues with high metabolic rates often use lipids, as well as glucose, for energy, conferring a survival advantage during feast and famine(1). Current dogma suggests that high-energy-consuming photoreceptors depend on glucose(2,3). Here we show that the retina also uses fatty acid beta-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(4) and is expressed in other tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acid(5,6). In the retinas of Vldlr(-/-) mice with low fatty acid uptake(6) 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 alpha-ketoglutarate (alpha-KG). Low alpha-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)(7), 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.

• 出版日期2016-4