title: Phagocytosis-dependent ketogenesis in retinal pigment epithelium.
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 theMreg-/-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 theAbca4-/-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.
authors.affiliation: From the Department of Biochemistry, School of Dental Medicine (SDM), University of Pennsylvania, Philadelphia, Pennsylvania 19104 and.
authors.forename: Juan
authors.initials: J
authors.lastname: Reyes-Reveles
authors.affiliation: From the Department of Biochemistry, School of Dental Medicine (SDM), University of Pennsylvania, Philadelphia, Pennsylvania 19104 and.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Dhingra
authors.affiliation: From the Department of Biochemistry, School of Dental Medicine (SDM), University of Pennsylvania, Philadelphia, Pennsylvania 19104 and.
authors.forename: Desiree
authors.initials: D
authors.lastname: Alexander
authors.affiliation: From the Department of Biochemistry, School of Dental Medicine (SDM), University of Pennsylvania, Philadelphia, Pennsylvania 19104 and.
authors.forename: Alvina
authors.initials: A
authors.lastname: Bragin
authors.affiliation: the Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19146 nancy.philp@jefferson.edu.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Philp
authors.affiliation: From the Department of Biochemistry, School of Dental Medicine (SDM), University of Pennsylvania, Philadelphia, Pennsylvania 19104 and battagli@upenn.edu.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Boesze-Battaglia
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D003470:Culture Media; D005260:Female; D005838:Genotype; D006801:Humans; D007659:Ketones / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism*
chemical_list: D003470:Culture Media; D007659:Ketones; D008055:Lipids; D010100:Oxygen; D020155:3-Hydroxybutyric Acid
keywords: fatty acid; lipid metabolism; phagocytosis; photoreceptor; photosynthesis; retinal metabolism