Journal Article

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

Hurst, Christian G, Fruttiger, Marcus, Evans, Lucy P, Vevis, Kristis, Gantner, Marin L, Bherer, Patrick, Levy, Emile, Rezende, Flavio A, Powner, Michael B, Smith, Lois E H, Maranda, Bruno, Packard, Alan, Sapieha, Przemyslaw, Burnim, Samuel, Kim, Jin Sung, Patel, Gauri, Sun, Ye, Juan, Aimee M, Hatton, Colman J, Cui, Zhenghao, Fu, Zhongjie, Joyal, Jean-Sébastien, Fredrick, Thomas, Pierce, Kerry A, Aguilar, Edith, Shao, Zhuo, Saba, Nicholas, Clish, Clary B, Boisvert, Michel, Chen, Jing, Friedlander, Martin

2016

Overview

Retinal neovascularization, as occurs in age-related macular degeneration, may result from an increase in VEGFA levels due to dysregulated lipid and glucose metabolism within photoreceptors. 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 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 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 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) 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 14 / 14/28 / 59 / 59/78 / 631/378/2607 / 631/378/2613/1786 / 631/443/319/333/1465 / 64 / 64/60 / 692/308/575 / Angiogenesis / Animals / Biomedicine / Cancer Research / Development and progression / Famine / Fatty acids / Fatty Acids - metabolism / Gene Expression Regulation / Glucose / Glucose - metabolism / Health aspects / Humans / Hypoxia / Infectious Diseases / Ketoglutaric Acids - metabolism / letter / Lipid metabolism / Lipid Metabolism - genetics / Lipids / Macular degeneration / Macular Degeneration - genetics / Macular Degeneration - metabolism / Macular Degeneration - pathology / Metabolic Diseases / Metabolism / Mice / Molecular Medicine / Neovascularization / Neurosciences / Oxidation / Oxidation-Reduction / Photoreception / Photoreceptor Cells - metabolism / Photoreceptor Cells - pathology / Physiological aspects / Receptors, G-Protein-Coupled - biosynthesis / Receptors, G-Protein-Coupled - genetics / Receptors, LDL - genetics / Receptors, LDL - metabolism / Retina / Retina - metabolism / Retina - pathology / Retinal diseases / Retinal Neovascularization - genetics / Retinal Neovascularization - metabolism / Retinal Neovascularization - pathology / Risk factors / Sensors / Vascular Endothelial Growth Factor A - genetics / Vascular Endothelial Growth Factor A - metabolism