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. 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

Jean-Sébastien Joyal  1   2   3 , Ye Sun  4 , Marin L Gantner  5 , Zhuo Shao  4 , Lucy P Evans  4 , Nicholas Saba  4 , Thomas Fredrick  4 , Samuel Burnim  4 , Jin Sung Kim  3 , Gauri Patel  2 , Aimee M Juan  4 , Christian G Hurst  4 , Colman J Hatton  4 , Zhenghao Cui  4 , Kerry A Pierce  6 , Patrick Bherer  7 , Edith Aguilar  8 , Michael B Powner  9 , Kristis Vevis  9 , Michel Boisvert  10 , Zhongjie Fu  4 , Emile Levy  10 , Marcus Fruttiger  9 , Alan Packard  11 , Flavio A Rezende  12 , Bruno Maranda  7 , Przemyslaw Sapieha  12 , Jing Chen  4 , Martin Friedlander  8 , Clary B Clish  6 , Lois E H Smith  4
Affiliations

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

Jean-Sébastien Joyal et al. Nat Med. 2016 Apr.

Erratum in

  • Corrigendum: Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1.
    Joyal JS, Sun Y, Gantner ML, Shao Z, Evans LP, Saba N, Fredrick T, Burnim S, Kim JS, Patel G, Juan AM, Hurst CG, Hatton CJ, Cui Z, Pierce KA, Bherer P, Aguilar E, Powner MB, Vevis K, Boisvert M, Fu Z, Levy E, Fruttiger M, Packard A, Rezende FA, Maranda B, Sapieha P, Chen J, Friedlander M, Clish CB, Smith LE. Joyal JS, et al. Nat Med. 2016 Jun 7;22(6):692. doi: 10.1038/nm0616-692a. Nat Med. 2016. PMID: 27270778 No abstract available.

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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Figures

Figure 1
Figure 1. Retinal energy deficits are associated with vascular lesions in Vldlr−/−
(a) Pathologic vessels in Vldlr−/− retinas originated from the deep vascular plexus (DVP) and breached the outer plexiform layer (P12), extending towards photoreceptor outer segments (os) at P16. Scale: 200 µm. n = 5 retinas. (b) Vldlr−/− pups raised in darkness (n = 10 retinas) compared to normal 12 hours light/dark cycle (Ctl: control, n = 28) to increase retinal energy demands. Scale: 1 mm (left), 0.5 mm (others). White spots label vascular lesions. P = 0.0031. (c) Mitochondrial volume quantified by 3D reconstruction of retinal scanning electron microscopy (SEM) images. Mitochondria within photoreceptors are pseudo-colored. n = 23 photoreceptors. Scale: 5µm. P < 0.0001. (d) Retinal ATP level was significantly lower in Vldlr−/− retina (n = 6) compared to littermate control wild type retinas (WT; n = 4). P = 0.0026. Results are presented as mean ± SEM. Two-tailed Student t-test; ** P < 0.01, *** P < 0.001.
Figure 2
Figure 2. Dual lipid and glucose fuel deficiency in Vldlr−/− retinas
(a) Oxygen consumption rate (OCR) and (b) maximal OCR of wild type (WT) retinas provided with long-chain fatty acid (FA) palmitate or control (Ctl: bovine serum albumin or BSA) in the presence or absence of FA oxidation inhibitor, etomoxir (40 µM). n = 6–8 retinas. (c) Circulating plasma palmitate levels in WT and Vldlr−/− mice. n = 7 WT, 13 Vldlr−/− mice plasma samples. P<0.0001. (d) Metabolite array of FA β-oxidation, (e) total acylcarnitine (P = 0.0108) and free carnitine levels (P = 0.0014) measured by LC/MS/MS. n = 3 animal retinas. (f) Cpt1a mRNA expression of intact retinas (left; P = 0.0052) and laser capture microdissected (LCM) retinal layers by qRT-PCR. ONL: outer nuclear (photoreceptors); INL: inner nuclear and GCL: ganglion cell layers. n = 3 animal retinas. (g) 18F-FDG microPET and CT scan revealed decreased glucose uptake in Vldlr−/− retinas, confirmed by retinal gamma radioactivity counts. Scale: 4 mm. n = 22 WT, 12 Vldlr−/− retinas, P = 0.0116. (h) Glut1 mRNA expression in intact retinas (left, n = 9 WT, 12 Vldlr−/− retinas; P = 0.0119) and retinal layers (right) by LCM and qRT-PCR (n = 3 retinas). (i) Glut1 protein expression of intact WT and Vldlr−/− retina. n = 6 retinas, P = 0.030. Results are presented as mean ± SEM. Two-tailed Student t-test (c–f, g–i) and one-way ANOVA with Tukey post-hoc analysis (b,f,h); * P < 0.05, ** P < 0.01, *** P < 0.001.
Figure 3
Figure 3. Ffar1 modulates retinal glucose uptake and RAP
(a) Decreased lipid uptake in Vldlr−/− retina increased extracellular mid/long chain FA, the agonist of lipid sensor Ffar1, which was associated with reduced Glut1 expression. (b) Expression of FA sensing GPCR in WT and Vldlr−/− intact retinas and (c) Ffar1 distribution in retinal layers by LCM (qRT-PCR). ONL: outer nuclear layer, INL: inner nuclear layer, GCL: ganglion cell layer. n = 3 animal retinas. (d) Glucose uptake (3H-2-DG tracer; n = 5–8 ctl, 9–16 GW-treated retinas), (e) Glut1 protein expression (n = 12 retinas, P < 0.0001) and (f) number of RAP-like pathologic vascular lesions at P16 in WT and Vldlr−/− mice treated with Ffar1 agonist GW9508 (GW; n = 11) or vehicle (ctl; n = 7, P = 0.0002). (g) Glucose uptake (18F-FDG; n = 4 retinas, scale: 4 mm), (h) Glut1 protein expression (n = 10 WT, others 9 retinas), and (i) number of RAP-like pathologic vascular lesions of WT (no lesions) and Vldlr−/− mice compared to littermate Vldlr−/−/Ffar1+/+ mice (P16; n = 10 retinas, P = 0.0153). Results are presented as mean ± SEM. Two-tailed Student t-test (e,f,i) and one-way ANOVA with Dunnett’s (b,c,g,h) or Tukey’s (d) post-hoc comparison; * P < 0.05, ** P < 0.01, *** P < 0.001.
Figure 4
Figure 4. Fuel deficient Vldlr−/− retina generates less α-Ketoglutarate and more Vegf
(a) Dual shortage of glucose (b, pyruvate; n = 15 WT, 12 Vldlr−/− retinas P = 0.0032) and FA uptake reduces acetyl-coA (c, estimated by measuring acetylcarnitine; n = 3, P = 0.0094) and (d) TCA (Krebs) cycle intermediate α-KG in Vldlr−/− retina (LC/MS/MS; n = 11 WT, 15 Vldlr−/− retinas, P = 0.0069). Together with oxygen (O2), α-KG is an essential co-activator of propyl-hydroxylase dehydrogenase (PHD) that tags HIF-1α for degradation by proline hydroxylation (hydroxyproline). (e) Levels of hydroxyproline residues in WT and Vldlr−/− retinas measured by LC/MS/MS (n = 15 WT, 12 Vldlr−/− animal retinas, P = 0.0004) and (f) Hif1a stabilization of WT, Vldlr−/− and Vldlr−/−/Ffar1−/− retinal nuclear extractions. We used Fibrillarin (Fbl) as nuclear loading control. n = 3 all groups. (g) Hif1a retinal expression in Vldlr−/− photoreceptor layer (P12 retinal flat mounts, Scale: 100 µm; left: extended focus; middle and right panels: 3D confocal IHC, n = 3) where (h) Vegfa was then also secreted (P16, ELISA, n = 6 retinas) and (i) localized (P16 retinal flat mounts, Scale: 100 µm; left: extended focus; middle and right panels: 3D confocal IHC, n = 3 retinas). (j) Human subjects with AMD, either retinal angiomatous proliferation (RAP, n = 3) or choroidal neovascularization (CNV, n = 7) had higher VEGFA vitreous levels by ELISA compared to control subjects without pathologic neovessels (macular hole; n = 8). Results are presented as mean ± SEM. Two-tailed Student t-test (c,d), Mann Whitney test (b,e), and one-way ANOVAs with post-hoc Dunett’s (f,j) or Tukey’s multiple comparison (h); * P < 0.05, ** P < 0.01, *** P < 0.001.
See this image and copyright information in PMC

Comment in

  • Burning fat fuels photoreceptors.
    Rajala RV, Gardner TW. Rajala RV, et al. Nat Med. 2016 Apr;22(4):342-3. doi: 10.1038/nm.4080. Nat Med. 2016. PMID: 27050587 No abstract available.

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