Triglyceride-derived fatty acids reduce autophagy in a model of retinal angiomatous proliferation
Emilie Heckel, Gael Cagnone, Tapan Agnihotri, Bertan Cakir, Ashim Das, Jin Sung Kim, Nicholas Kim, Geneviève Lavoie, Anu Situ, Sheetal Pundir, Ye Sun, Florian Wünnemann, Kerry A. Pierce, Courtney Dennis, Grant A. Mitchell, Sylvain Chemtob, Flavio A. Rezende, Gregor Andelfinger, Clary B. Clish, Philippe P. Roux, Przemyslaw Sapieha, Lois E.H. Smith, Jean-Sébastien Joyal
Emilie Heckel, Gael Cagnone, Tapan Agnihotri, Bertan Cakir, Ashim Das, Jin Sung Kim, Nicholas Kim, Geneviève Lavoie, Anu Situ, Sheetal Pundir, Ye Sun, Florian Wünnemann, Kerry A. Pierce, Courtney Dennis, Grant A. Mitchell, Sylvain Chemtob, Flavio A. Rezende, Gregor Andelfinger, Clary B. Clish, Philippe P. Roux, Przemyslaw Sapieha, Lois E.H. Smith, Jean-Sébastien Joyal
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Research Article Ophthalmology Vascular biology

Triglyceride-derived fatty acids reduce autophagy in a model of retinal angiomatous proliferation

Abstract

Dyslipidemia and autophagy have been implicated in the pathogenesis of blinding neovascular age-related macular degeneration (NV-AMD). VLDL receptor (VLDLR), expressed in photoreceptors with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acids. Since fatty acid uptake is reduced in Vldlr–/– tissues, more remain in circulation, and the retina is fuel deficient, driving the formation in mice of neovascular lesions reminiscent of retinal angiomatous proliferation (RAP), a subtype of NV-AMD. Nutrient scarcity and energy failure are classically mitigated by increasing autophagy. We found that excess circulating lipids restrained retinal autophagy, which contributed to pathological angiogenesis in the Vldlr–/– RAP model. Triglyceride-derived fatty acid sensed by free fatty acid receptor 1 (FFAR1) restricted autophagy and oxidative metabolism in photoreceptors. FFAR1 suppressed transcription factor EB (TFEB), a master regulator of autophagy and lipid metabolism. Reduced TFEB, in turn, decreased sirtuin-3 expression and mitochondrial respiration. Metabolomic signatures of mouse RAP-like retinas were consistent with a role in promoting angiogenesis. This signature was also found in human NV-AMD vitreous. Restoring photoreceptor autophagy in Vldlr–/– retinas, either pharmacologically or by deleting Ffar1, enhanced metabolic efficiency and suppressed pathological angiogenesis. Dysregulated autophagy by circulating lipids might therefore contribute to the energy failure of photoreceptors driving neovascular eye diseases, and FFAR1 may be a target for intervention.

Authors

Emilie Heckel, Gael Cagnone, Tapan Agnihotri, Bertan Cakir, Ashim Das, Jin Sung Kim, Nicholas Kim, Geneviève Lavoie, Anu Situ, Sheetal Pundir, Ye Sun, Florian Wünnemann, Kerry A. Pierce, Courtney Dennis, Grant A. Mitchell, Sylvain Chemtob, Flavio A. Rezende, Gregor Andelfinger, Clary B. Clish, Philippe P. Roux, Przemyslaw Sapieha, Lois E.H. Smith, Jean-Sébastien Joyal

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Figure 7

Enhancing autophagy rescues pathological angiogenesis and improves vision.

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Enhancing autophagy rescues pathological angiogenesis and improves visio...
(A) Retinal autophagy flux quantification of CAG-RFP-EGFP-LC3/Vldlr–/– mice treated with HPβCD (8 g/kg per day for 8 days; n = 7 retinas) compared with vehicle-treated mice (Veh; n = 6 retinas) at P16. ONL, outer nuclear layer; IS, photoreceptor inner segment; OS, photoreceptor outer segment. Scale bars: 10 μm. (B) mRNA expression in Vldlr–/– retinas of pups treated with HPβCD or vehicle. n = 8–12 retinas per group. (C and D) Oxygen consumption rate (OCR) and ATP-derived respiration of 661W cells treated 8 hours with palmitate or vehicle (BSA alone) in the presence or absence of drugs that raise (C) (HPβCD; 1 mM) or inhibit (D) (chloroquine, CQ; 40 μM) autophagy. n = 6–8 experiments per group. (E) Quantification of RAP-like vascular lesions (white spots) in retinal flat mounts of Vldlr–/– mice treated with HPβCD (n = 6 retinas) or vehicle (Veh, n = 7 retinas) at P16. Scale bars:1 mm. Data are represented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. One-way ANOVA with Tukey’s multiple-comparison test and 2-tailed Student’s t test. See also Supplemental Figure 7.