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

Abstract

Tissues with high metabolic rates often use lipid as well as glucose for energy, conferring a survival advantage during feast and famine.1 Current dogma suggests that high-energy consuming photoreceptors depend on glucose.2,3 Here we show that retina also uses fatty acids (FA) β-oxidation for energy. Moreover, we identify a lipid sensor Ffar1 that curbs glucose uptake when FA are available. Very low-density lipoprotein receptor (VLDLR), expressed in tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived FA.4,5 Vldlr is present in photoreceptors.6 In Vldlr−/− retinas, Ffar1, sensing high circulating lipid levels despite decreased FA uptake5, suppresses glucose transporter Glut1. This impaired glucose entry into photoreceptors results in a dual lipid/glucose fuel shortage and reduction in the Krebs cycle intermediate α-ketoglutarate (KG). Low α-KG levels promote hypoxia-induced factor-1α (Hif1a) stabilization and vascular endothelial growth factor (Vegfa) secretion by starved Vldlr−/− photoreceptors, attracting neovessels to supply fuel. These aberrant vessels invading normally avascular photoreceptors in Vldlr−/− retinas are reminiscent of retinal angiomatous proliferation (RAP), a subset of neovascular age-related macular degeneration (AMD)7, associated with high vitreous VEGF levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in neovascular AMD and other retinal diseases.

Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism

“…If the glucose-fatty acid cycle helps elucidate preferential substrate metabolism inside the cell based on relative abundance, it fails to adequately explain how nutrient uptake is regulated at the cell surface to redirect unwanted fuel to distant storage locations, such as liver or adipocytes. The control mechanisms for substrate selection in the retina have not yet been fully determined although we found that high circulating lipids signal through Ffar1 to suppress glut 1 and glucose uptake in the retina (Joyal et al, 2016). …”

“…Microglial cells also contribute to VEGF secretion and pathological angiogenesis, which is reviewed elsewhere (Binet and Sapieha, 2015; Guillonneau et al, 2017). Similarly in the outer retina, excessive expression of VEGF by photoreceptors and RPE contributes to the subretinal neovascularization that characterizes wet AMD, discussed in more detail later (Campochiaro, 2015; Grisanti and Tatar, 2008; Joyal et al, 2016; Ohno-Matsui et al, 2002; Witmer et al, 2003). …”

“…However, this reaction accounts for less than 20% of the ATP production in the retina, indicating that mitochondrial OXPHOS generates the vast majority of ATP using only a small portion of the glucose taken up. Therefore, alternative carbon substrates such as lipids can contribute to OXPHOS and ATP production (Joyal et al, 2016). …”

“…VLDLR deficient mice have reduced uptake of fatty acids and decreased fatty acyl intermediates of β-oxidation (Fig. 4d,g,h) resulting in early vascular changes, secondary to energy deficits (Joyal et al, 2016). VLDLR deficient retinas exposed to palmitate increase their oxygen consumption, which is prevented by blocking fatty acid beta oxidation (by inhibiting CPT1 with etomoxir; Fig.…”

“…However, Cohen and Noell concluded in 1960 that a substantial portion of the energy produced through oxidation by the retina (around 65%) was not derived from glucose (Cohen and Noell, 1960). We recently showed that the retina (photoreceptors) can also oxidize lipid through fatty acid β-oxidation to produce ATP, accounting for the energy gap noted by Cohen (Joyal et al, 2016). Little is known about lipid versus glucose fuel substrate preference and its importance during retinal development and pathology.…”