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

Academic Article
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Overview

authors

  • Joyal, J. S.
  • Sun, Y.
  • Gantner, Marin
  • Shao, Z.
  • Evans, L. P.
  • Saba, N.
  • Fredrick, T.
  • Burnim, S.
  • Kim, J. S.
  • Patel, G.
  • Juan, A. M.
  • Hurst, C. G.
  • Hatton, C. J.
  • Cui, Z.
  • Pierce, K. A.
  • Bherer, P.
  • Aguilar, E.
  • Powner, M. B.
  • Vevis, K.
  • Boisvert, M.
  • Fu, Z.
  • Levy, E.
  • Fruttiger, M.
  • Packard, A.
  • Rezende, F. A.
  • Maranda, B.
  • Sapieha, P.
  • Chen, J.
  • Friedlander, Martin
  • Clish, C. B.
  • Smith, L. E. H.

publication date

  • 2016

journal

  • Nature Medicine  Journal

abstract

  • 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.

subject areas

  • Animals
  • Fatty Acids
  • Gene Expression Regulation
  • Glucose
  • Humans
  • Ketoglutaric Acids
  • Lipid Metabolism
  • Macular Degeneration
  • Mice
  • Oxidation-Reduction
  • Photoreceptor Cells
  • Receptors, G-Protein-Coupled
  • Receptors, LDL
  • Retina
  • Retinal Neovascularization
  • Vascular Endothelial Growth Factor A
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Identity

PubMed Central ID

  • PMC4823176

International Standard Serial Number (ISSN)

  • 1078-8956

Digital Object Identifier (DOI)

  • 10.1038/nm.4059

PubMed ID

  • 26974308
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Additional Document Info

start page

  • 439

end page

  • 445

volume

  • 22

issue

  • 4

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