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Jeffrey Adijanto, Erin Seifert, Cynthia Moffat, Arvydas Maminishkis, Nancy Philp; Metabolic Coupling Between the Retinal Pigment Epithelium (RPE) and Retina. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2649.
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The retina is among the most metabolically active tissue in the body and its activity is sustained by nutrients delivered by the RPE from the choroidal blood supply. It is known that the outer retina converts more than 80% of glucose consumed into lactate, thus it releases large quantities of lactate that are taken up by the RPE. In our search for a mechanism through which the RPE could support the metabolic activity of the retina, we found that RPE cells are enriched in key enzymes (mRNA) involved in ketogenesis, to a level that rivals that in the liver. With mounting evidence that support a role for lactate as an energy substrate, it became of interest to determine if the RPE could use retina-derived lactate for oxidative metabolism and ketogenesis.
Human fetal RPE (hfRPE) grown on transwells (Maminishkis et al., IOVS, 2006) were used as a model system. Lactate or pyruvate (2.5 mM)-induced changes in O2 consumption and extracellular acidification rates (OCR and ECAR) of hfRPE cells were measured using the Seahorse analyzer XF24. β-hydroxybutyrate (β-HB) released into apical and basal chambers of differentiated hfRPE cells on transwells (24 hrs) was measured using a β-HB assay kit (Sigma).
We found that in the presence of glucose, addition of lactate or pyruvate to hfRPE cells induced a dramatic increase in OCR, which reflects oxidative respiration rate. This change is accompanied by a decrease in ECAR, which mostly correspond to a decreased rate of lactate production. In addition to oxidative metabolism, we show that hfRPE cells can also use lactate to generate β-HB, which is released into both its apical and basal compartments. The release of β-HB by hfRPE cells is consistent with the high mRNA expression of a recently identified β-HB transporter, MCT7 (SLC16A6), as well as the expression of key genes involved in ketogenesis, including BDH2 and HMGCS2.
Our experiments support a hypothesis whereby the RPE not only transports lactate out of the retina, but also uses it as an oxidative substrate. Additionally, the RPE converts lactate to β-HB that could be used by photoreceptors as an alternative metabolic substrate to support the high energy demands of phototransduction.
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