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

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

Author information

1
Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montreal, Quebec, Canada.
2
Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada.
3
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
4
Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
5
Lowy Medical Research Institute, La Jolla, California, USA.
6
Metabolite Profiling Platform, The Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.
7
Department of Genetics, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
8
Department of Cell and Molecular Biology, Scripps Research Institute, La Jolla, California, USA.
9
Institute of Ophthalmology, University College London, London, UK.
10
Department of Nutrition, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montreal, Montreal, Quebec, Canada.
11
Department of Radiology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts. USA.
12
Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec, Canada.

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.

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PMID:
26974308
PMCID:
PMC4823176
DOI:
10.1038/nm.4059
[Indexed for MEDLINE]
Free PMC Article

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