title: Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1.
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.
authors.affiliation: 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.|Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Joyal
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Lowy Medical Research Institute, La Jolla, California, USA.
authors.forename: Marin L
authors.initials: ML
authors.lastname: Gantner
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Lucy P
authors.initials: LP
authors.lastname: Evans
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Saba
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fredrick
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Burnim
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Jin Sung
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Gauri
authors.initials: G
authors.lastname: Patel
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Juan
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Hurst
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Colman J
authors.initials: CJ
authors.lastname: Hatton
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Zhenghao
authors.initials: Z
authors.lastname: Cui
authors.affiliation: Metabolite Profiling Platform, The Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Pierce
authors.affiliation: Department of Genetics, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bherer
authors.affiliation: Department of Cell and Molecular Biology, Scripps Research Institute, La Jolla, California, USA.
authors.forename: Edith
authors.initials: E
authors.lastname: Aguilar
authors.affiliation: Institute of Ophthalmology, University College London, London, UK.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Powner
authors.affiliation: Institute of Ophthalmology, University College London, London, UK.
authors.forename: Kristis
authors.initials: K
authors.lastname: Vevis
authors.affiliation: Department of Nutrition, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montreal, Montreal, Quebec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Boisvert
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Department of Nutrition, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montreal, Montreal, Quebec, Canada.
authors.forename: Emile
authors.initials: E
authors.lastname: Levy
authors.affiliation: Institute of Ophthalmology, University College London, London, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fruttiger
authors.affiliation: Department of Radiology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts. USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Packard
authors.affiliation: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Flavio A
authors.initials: FA
authors.lastname: Rezende
authors.affiliation: Department of Genetics, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Maranda
authors.affiliation: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cell and Molecular Biology, Scripps Research Institute, La Jolla, California, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Friedlander
authors.affiliation: Metabolite Profiling Platform, The Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Clary B
authors.identifier: http://orcid.org/0000-0001-8259-9245
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
mesh_terms: D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010084:Oxidation-Reduction; D010786:Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D007656:Ketoglutaric Acids; D043562:Receptors, G-Protein-Coupled; D011973:Receptors, LDL; C036053:VLDL receptor; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D005947:Glucose