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

Nat Med. 2016 Apr;22(4):439-45. doi: 10.1038/nm.4059. Epub 2016 Mar 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Fatty Acids
  • Ketoglutaric Acids
  • Receptors, G-Protein-Coupled
  • Receptors, LDL
  • VLDL receptor
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Glucose