title: The retinal pigment epithelium utilizes fatty acids for ketogenesis.
abstract: Every day, shortly after light onset, photoreceptor cells shed approximately a tenth of their outer segment. The adjacent retinal pigment epithelial (RPE) cells phagocytize and digest shed photoreceptor outer segment, which provides a rich source of fatty acids that could be utilized as an energy substrate. From a microarray analysis, we found that RPE cells express particularly high levels of the mitochondrial HMG-CoA synthase 2 (Hmgcs2) compared with all other tissues (except the liver and colon), leading to the hypothesis that RPE cells, like hepatocytes, can produce β-hydroxybutyrate (β-HB) from fatty acids. Using primary human fetal RPE (hfRPE) cells cultured on Transwell filters with separate apical and basal chambers, we demonstrate that hfRPE cells can metabolize palmitate, a saturated fatty acid that constitutes .15% of all lipids in the photoreceptor outer segment, to produce β-HB. Importantly, we found that hfRPE cells preferentially release β-HB into the apical chamber and that this process is mediated primarily by monocarboxylate transporter isoform 1 (MCT1). Using a GC-MS analysis of (13)C-labeled metabolites, we showed that retinal cells can take up and metabolize (13)C-labeled β-HB into various TCA cycle intermediates and amino acids. Collectively, our data support a novel mechanism of RPE-retina metabolic coupling in which RPE cells metabolize fatty acids to produce β-HB, which is transported to the retina for use as a metabolic substrate.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Adijanto
authors.forename: Jianhai
authors.initials: J
authors.lastname: Du
authors.forename: Cynthia
authors.initials: C
authors.lastname: Moffat
authors.forename: Erin L
authors.initials: EL
authors.lastname: Seifert
authors.forename: James B
authors.initials: JB
authors.lastname: Hurle
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Philp
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002952:Citric Acid Cycle / Q000502:physiology; D005136:Eye Proteins / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism*; D008297:Male; D051379:Mice; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D020155:3-Hydroxybutyric Acid; D005136:Eye Proteins; D005227:Fatty Acids; D006904:Hydroxymethylglutaryl-CoA Synthase; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1