Abstract
Daily, the retinal pigment epithelium (RPE) ingests a bolus of lipid and protein in the form of phagocytized photoreceptor outer segments (OS). The RPE, like the liver, expresses enzymes required for fatty acid oxidation and ketogenesis. This suggests that these pathways play a role in the disposal of lipids from ingested OS, as well as providing a mechanism for recycling metabolic intermediates back to the outer retina. In this study, we examined whether OS phagocytosis was linked to ketogenesis. We found increased levels of β-hydroxybutyrate (β-HB) in the apical medium following ingestion of OS by human fetal RPE and ARPE19 cells cultured on Transwell inserts. No increase in ketogenesis was observed following ingestion of oxidized OS or latex beads. Our studies further defined the connection between OS phagocytosis and ketogenesis in wild-type mice and mice with defects in phagosome maturation using a mouse RPE explant model. In explant studies, the levels of β-HB released were temporally correlated with OS phagocytic burst after light onset. In the Mreg-/- mouse where phagosome maturation is delayed, there was a temporal shift in the release of β-HB. An even more pronounced shift in maximal β-HB production was observed in the Abca4-/- RPE, in which loss of the ATP-binding cassette A4 transporter results in defective phagosome processing and accumulation of lipid debris. These studies suggest that FAO and ketogenesis are key to supporting the metabolism of the RPE and preventing the accumulation of lipids that lead to oxidative stress and mitochondrial dysfunction.
Highlights
The retinal pigment epithelium (RPE) ingests a bolus of lipid and protein in the form of phagocytized photoreceptor outer segments (OS)
The RPE has a daily diet of fatty acid rich OS that could provide substrates for fatty acid -oxidation (FAO) and ketogenesis
The participation of the RPE in photoreceptor renewal has been known for almost 50 years
Summary
Homeostasis in the outer retina through transport of nutrients and waste products [1, 2]. Individual RPE cells phagocytose numerous OS daily; in the central mouse retina, each RPE cell digests the contents of over 200 photoreceptor outer segment tips daily [5] These ingested OS provide a rich source of fatty acids (6 – 8) for the RPE, suggesting that fatty acid -oxidation (FAO) could support the energy demands of the RPE, sparing glucose for the outer retina [9]. Our own in vitro studies have demonstrated that human RPE cells can use palmitate (16:0), a major lipid component of OS for FAO [15] Use of these nutrients as metabolic substrates requires enzymes essential for FAO, including carnitine palmitoyl transferase 1A and the trifunctional protein complex, both of which are expressed in mouse and human RPE [16]. Ketone body release was found to depend on diurnal phagocytosis of OS with defects in phagosome maturation contributing to metabolic delay as demonstrated in our mouse RPE explant models
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