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Cited by 264

The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.

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

Open access
Joyal, Jean-Sébastien, Sun, Ye, Gantner, Marin L, Shao, Zhuo, Evans, Lucy P, Saba, Nicholas, Fredrick, Thomas, Burnim, Samuel, Kim, Jin Sung, Patel, Gauri, Juan, Aimee M, Hurst, Christian G, Hatton, Colman J, Cui, Zhenghao, Pierce, Kerry A, Bherer, Patrick, Aguilar, Edith, Powner, Michael B, Vevis, Kristis, Boisvert, Michel, Fu, Zhongjie, Levy, Emile, Fruttiger, Marcus, Packard, Alan, Rezende, Flavio A, Maranda, Bruno, Sapieha, Przemyslaw, Chen, Jing, Friedlander, Martin, Clish, Clary B, Smith, Lois E H·2016·Nature Medicine
DOI 10.1038/nm.4059
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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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Metadata

Authors
Joyal, J.-S., Sun, Y., Gantner, M. L., 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, M., Clish, C. B., & Smith, L. E. H.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2016-03-14
Volume
22
Issue
4
Pages
439-445
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.4059
OpenAlex
W2298457819
Cited by
264
References
56
FWCI
21.29
Type
journal article
Language
en
Open access
green

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