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

Émilie Heckel ,Grant A Mitchell,Kerry A Pierce,Tapan Agnihotri,Sheetal Pundir,Sylvain Chemtob,Ye Sun,Geneviève Lavoie,Anu Situ,Ashim Das,Jin Sung Kim,Bertan Cakir,Philippe P Roux,Nicholas Kim,Florian Wünnemann,Courtney Dennis,Clary B Clish,Przemysław Sapieha ,Flávio Rezende ,Lois E H Smith ,Grégor Andelfinger ,Gaël Cagnone ,Jean‐Sébastien Joyal

doi:10.1172/jci.insight.154174

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.

Highlights

Neovascular AMD is the leading cause of vision loss in aging adults, and retinal angiomatous proliferation (RAP) occurs in 12-15 % of neovascular age-related macular degeneration (NV-AMD) subjects [1]
Autophagy is suppressed in the Vldlr-/- mouse model of RAP-like neovascularization We previously showed that Vldlr–/– mice retinas develop RAP-like neovascular lesions that invade the energy-deficient photoreceptor outer nuclear layer (Figure 1A) [6]
Gene set enrichment analysis (GSEA) for autophagosome formation was significantly suppressed in Vldlr–/– photoreceptors compared to WT (Figure S2C)

Summary

Introduction

Neovascular AMD is the leading cause of vision loss in aging adults, and RAP occurs in 12-15 % of NV-AMD subjects [1]. Diseases of the macula, such as AMD, are likely to be more susceptible to dysregulations in energy metabolism. The macula contains the highest cone photoreceptors density with abundant mitochondria and high energy requirements [2, 3]. A primary energy failure of photoreceptors was hypothesized to signal an increase in vascular supply to offset unmet neuronal energy demands in NV-AMD. We recently showed that fatty acids (FA) could be oxidized by photoreceptors [6]. The origin of these lipids is unknown, but a potential source is intracellular substrates controlled by autophagy. Dyslipidemia [8] and disrupted autophagy [9, 10] have been previously associated with AMD, their role in the etiology of vascular disease has not been established

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