Triglyceride-derived Fatty Acids Reduce Autophagy in a Model of Retinal Angiomatous Proliferation

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2022 Feb 15

PMID 35167498

Authors

Emilie Heckel

Gael Cagnone

Tapan Agnihotri

Bertan Cakir

Ashim Das

Jin Sung Kim

Nicholas Kim

Genevieve Lavoie

Anu Situ

Sheetal Pundir

Ye Sun

Florian Wunnemann

Kerry A Pierce

Courtney Dennis

Grant A Mitchell

Sylvain Chemtob

Flavio A Rezende

Gregor Andelfinger

Clary B Clish

Philippe P Roux

Przemyslaw Sapieha

Lois Eh Smith

Jean-Sebastien Joyal

Affiliations

Soon will be listed here.

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.

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