PPAR? is essential for retinal lipid metabolism and neuronal survival.

ABSTRACT: BACKGROUNDPeroxisome proliferator activated receptor-alpha (PPAR?) is a ubiquitously expressed nuclear receptor. The role of endogenous PPAR? in retinal neuronal homeostasis is unknown. Retinal photoreceptors are the highest energy-consuming cells in the body, requiring abundant energy substrates. PPAR? is a known regulator of lipid metabolism, and we hypothesized that it may regulate lipid use for oxidative phosphorylation in energetically demanding retinal neurons.RESULTSWe found that endogenous PPAR? is essential for the maintenance and survival of retinal neurons, with Ppar? -/- mice developing retinal degeneration first detected at 8 weeks of age. Using extracellular flux analysis, we identified that PPAR? mediates retinal utilization of lipids as an energy substrate, and that ablation of PPAR? ultimately results in retinal bioenergetic deficiency and neurodegeneration. This may be due to PPAR? regulation of lipid transporters, which facilitate the internalization of fatty acids into cell membranes and mitochondria for oxidation and ATP production.CONCLUSIONWe identify an endogenous role for PPAR? in retinal neuronal survival and lipid metabolism, and furthermore underscore the importance of fatty acid oxidation in photoreceptor survival. We also suggest PPAR? as a putative therapeutic target for age-related macular degeneration, which may be due in part to decreased mitochondrial efficiency and subsequent energetic deficits.

SUBMITTER: Pearsall EA 

PROVIDER: S-EPMC5706156 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature