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

Nature Medicine volume 22, pages 439–445 (2016)Cite this article

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A Corrigendum to this article was published on 07 June 2016

This article has been updated

Abstract

Tissues with high metabolic rates often use lipids, as well as glucose, for energy, conferring a survival advantage during feast and famine1. Current dogma suggests that high-energy–consuming photoreceptors depend on glucose2,3. 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 photoreceptors4 and is expressed in other tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acid5,6. In the retinas of Vldlr−/− mice with low fatty acid uptake6 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.

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Figure 1: Retinal energy deficits are associated with vascular lesions in Vldlr−/− mice.
Figure 2: Dual lipid and glucose fuel deficiency in Vldlr−/− retinas.
Figure 3: Ffar1 modulates retinal glucose uptake and RAP.
Figure 4: Fuel-deficient Vldlr −/− retinas generate less α-KG and more Vegfa.

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Change history

  • 24 March 2016

    In the version of this article initially published online, there were two errors. There was a typographical error in the text, which should have stated that the 'dark current' is an electrochemical gradient required for photon-induced polarization (rather than depolarization, as incorrectly stated). In addition, some funding sources were inadvertently omitted from the Acknowledgments. The errors have been corrected for the print, PDF and HTML versions of this article.

  • 07 June 2016

    Nat. Med.; doi: 10.1038/nm.4059; corrected 24 March 2016 In the version of this article initially published online, there were two errors. There was a typographical error in the text, which should have stated that the 'dark current' is an electrochemical gradient required for photon-induced polarization (rather than depolarization, as incorrectly stated).

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Acknowledgements

This work was supported by the US National Institutes of Health (NIH) grants EY024864 (L.E.H.S.), EY017017 (L.E.H.S.), EY022275 (L.E.H.S.), P01 HD18655 (L.E.H.S.) and EY024963 (J.C.) and EY11254 (Friedlander), the Lowy Medical Research Institute (M. Friedlander, L.E.H.S. and M. Fruttiger), the European Commission FP7 project 305485 PREVENT-ROP (L.E.H.S.), a Burroughs Wellcome Fund Career Award for Medical Scientists (J.-S.J.), the Foundation Fighting Blindness (J.-S.J.), the Canadian Institute of Health Research (CIHR) grant 143077 (J.-S.J.), the Fonds de Recherche du Québec–Santé (FRQS) (J.-S.J.), the Canadian Child Health Clinician Scientist Program (J.-S.J.), a CIHR New Investigator Award (J.-S.J.), the Knights Templar Eye Foundation (Z.F.), the Bernadotte Foundation (Z.F.), the Canada Research chair and CIHR grant 221478 (P.S.), the Boston Children's Hospital Ophthalmology Foundation (J.C.), a Boston Children's Hospital Faculty Career Development Award (J.C.), the Bright Focus Foundation (J.C.) and the Massachussetts Lions Eye Research Fund, Inc. (J.C.). We thank M. Puder and P. Nandivada (Harvard Medical School, Boston Children's Hospital) for sharing the Ffar1−/− mice; M. Al-Ubaidi (University of Oklahoma) for sharing the 661W photoreceptor cells; Z. Lin and W.T. Pu (Harvard Medical School, Boston Children's Hospital) for sharing a modified CAG-GFP-miR30 construct; and C. Cepko (Harvard Medical School) and T. Li (National Eye Institute) for providing the pAAV-RK-GFP vector.

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Authors and Affiliations

  1. Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montreal, Quebec, Canada

    Jean-Sébastien Joyal

  2. Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada

    Jean-Sébastien Joyal & Gauri Patel

  3. Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada

    Jean-Sébastien Joyal & Jin Sung Kim

  4. Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA

    Ye Sun, Zhuo Shao, Lucy P Evans, Nicholas Saba, Thomas Fredrick, Samuel Burnim, Aimee M Juan, Christian G Hurst, Colman J Hatton, Zhenghao Cui, Zhongjie Fu, Jing Chen & Lois E H Smith

  5. Lowy Medical Research Institute, La Jolla, California, USA

    Marin L Gantner

  6. Metabolite Profiling Platform, The Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA

    Kerry A Pierce & Clary B Clish

  7. Department of Genetics, Université de Sherbrooke, Sherbrooke, Quebec, Canada

    Patrick Bherer & Bruno Maranda

  8. Department of Cell and Molecular Biology, Scripps Research Institute, La Jolla, California, USA

    Edith Aguilar & Martin Friedlander

  9. Institute of Ophthalmology, University College London, London, UK

    Michael B Powner, Kristis Vevis & Marcus Fruttiger

  10. Department of Nutrition, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montreal, Montreal, Quebec, Canada

    Michel Boisvert & Emile Levy

  11. Department of Radiology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA

    Alan Packard

  12. Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec, Canada

    Flavio A Rezende & Przemyslaw Sapieha

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  1. Jean-Sébastien Joyal
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Contributions

J.-S.J. and L.E.H.S. conceived and designed all experiments, and wrote the manuscript; and J.-S.J., Y.S., Z.S., L.P.E., N.S., T.F., S.B., J.S.K., G.P., A.M.J., C.G.H., C.J.H., Z.C. and Z.F. performed all in vivo and ex vivo experiments, except for those indicated below. M.L.G., E.A. and M. Friedlander performed and analyzed the Seahorse experiments; K.A.P. and C.B.C. performed and analyzed the metabolite profiling; P.B. and B.M. performed and analyzed fatty acid β-oxidation; M.B.P., K.V. and M. Fruttiger performed and analyzed 3D SEM; M.B. and E.L. analyzed lipid composition of plasma; F.A.R. collected human vitreous samples; P.S. measured human vitreous VEGF levels; C.B.C., M. Friedlander, J.C., P.S., B.M., F.A.R., A.P., M. Fruttiger and E.L. provided expert advice. All of the authors analyzed the data.

Corresponding authors

Correspondence to Jean-Sébastien Joyal or Lois E H Smith.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Supplementary Tables 1–2 (PDF 10547 kb)

WT photoreceptor mitochondria.

Video of pseudo-colored mitochondria in WT photoreceptors by 3D reconstruction of scanning electron microscopy (MOV 4894 kb)

Vldlr−/− photoreceptor mitochondria.

Video of pseudo-colored mitochondria in Vldlr−/− photoreceptors by 3D reconstruction of scanning electron microscopy. A vascular lesion (center) is pseudocoloured in green. (MOV 15200 kb)

Ffar1 dictates glucose uptake in Vldlr−/− retina.

[18F]FDG microPET / CT scan comparing glucose uptake simultaneously in WT (left), Vldlr−/− (middle left), Vldlr−/− /Ffar1−/− (middle right) and Ffar1−/− mice (right) (MPG 982 kb)

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Joyal, JS., Sun, Y., Gantner, M. et al. Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1. Nat Med 22, 439–445 (2016). https://doi.org/10.1038/nm.4059

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