The Retinal Pigment Epithelium Utilizes Fatty Acids for Ketogenesis: IMPLICATIONS FOR METABOLIC COUPLING WITH THE OUTER RETINA

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 beta-hydroxybutyrate (beta-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 approximate to 15% of all lipids in the photoreceptor outer segment, to produce beta-HB. Importantly, we found that hfRPE cells preferentially release beta-HB into the apical chamber and that this process is mediated primarily by monocarboxylate transporter isoform 1 (MCT1). Using a GC-MS analysis of C-13-labeled metabolites, we showed that retinal cells can take up and metabolize 13C-labeled beta-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 beta-HB, which is transported to the retina for use as a metabolic substrate.