PPARα is Essential for Retinal Neuronal Survival and Lipid Metabolism

Abstract

Purpose : The role of endogenous peroxisome proliferator-activated receptor-alpha (PPARα) in maintaining retinal neurons remains unknown, although activating PPARα reduces the incidence of proliferative diabetic retinopathy, a neurovascular disease. The purpose of this study was to determine if PPARα is important to retinal neuronal survival in endogenous conditions, and to delineate its role in retinal energy metabolism.

Methods : Electroretinograms (ERGs), optical coherence tomography and a cell death ELISA were used in wild-type (WT) and PPARα^-/- mice to determine if PPARα loss causes retinal neurodegeneration. Retinas from WT and PPARα^-/- mice were isolectin-stained to examine retinal vasculature. Nicotinamide adenine dinucleotide (NADH) oxidation assays were used to identify effects of PPARα on retinal energy metabolism. Rats were administered PPARα agonist fenofibrate, and oxygen consumption in retinal mitochondria was measured to determine if PPARα activation affects utilization of lipids as a substrate for ATP production. Mass spectrometry of retinal lysates was used to identify specific metabolic pathways regulated by PPARα in the retina.

Results : ERG response declined in PPARα^-/- mice relative to wild-type (WT) beginning at 8 weeks of age, as did total retinal thickness. Apoptosis was elevated in PPARα^-/- retinas relative to WT as early as 8 weeks. Retinal vasculature was unaffected by PPARα ablation. NADH-linked respiration was decreased in PPARα^-/- retinas and increased by fenofibrate in WT animals. Fenofibrate increased mitochondrial utilization of lipids as an oxidizable substrate for ATP production. Protein levels of mitochondrial lipid transporters were decreased in PPARα^-/- retinas, and glycolytic enzymes were increased, potentially to compensate for decreased lipid utilization.

Conclusions : Cumulatively, our data suggest that PPARα is critical for retinal neuronal survival, and to the ability to use lipids as a fuel source. These findings are important to basic retinal cell biology and to translational research, as we demonstrate for the first time that: (1) PPARα is essential for retinal neuronal survival in physiological conditions; (2) PPARα facilitates retinal utilization of lipids an energy substrate by regulating mitochondrial lipid transporters; and (3) PPARα is a new potential therapeutic target for age-related macular degeneration (AMD), which is due in part to decreased energy efficiency.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.