The identification of pathways necessary for photoreceptor and retinal pigment epithelium (RPE) function is critical to uncover blindness therapies. Here we report the discovery of adiponectin receptor 1 (AdipoR1) as a regulator of these cells’ functions. Docosahexaenoic acid (DHA) is avidly retained in photoreceptors, while mechanisms controlling DHA uptake and retention are unknown. Thus, we demonstrate that AdipoR1 ablation results in DHA reduction. In situ hybridization reveals photoreceptor and RPE cell AdipoR1 expression, blunted in AdipoR1−/− mice. We also find decreased photoreceptor-specific phosphatiydylcholine containing very long chain polyunsaturated fatty acids and severely-attenuated electroretinograms. These changes precede progressive photoreceptor degeneration in AdipoR1−/− mice. RPE-rich eyecup cultures from AdipoR1−/− reveal impaired DHA uptake. AdipoR1 overexpression in RPE cells enhances DHA uptake, whereas AdipoR1 silencing has the opposite effect. These results establish AdipoR1 as a regulatory switch of DHA uptake, retention, conservation, and elongation in photoreceptors and RPE, thus preserving photoreceptor cell integrity.

This article is available online at http://www.jlr.org RETINAL DEGENERATIVE DISEASESRetinal degenerative diseases are a complex group of conditions with different etiologies that result in a common outcome: photoreceptor apoptotic cell death ( 1-5 ). Accordingly, there are differences in how these conditions evolve. For instance, in retinitis pigmentosa (RP), rod photoreceptor death initially occurs in the periphery, whereas in age-related macular degeneration (AMD), death is initiated in the macular zone and spreads in later phases throughout the retina ( 2, 5 ). RP is a collection of inherited blinding diseases caused by the mutation of a wide variety of genes resulting in more than 150 abnormalities of photoreceptor-specifi c proteins, including mutations of rhodopsin, peripherin, the ␤ -subunit of cGMP phosphodiesterase, and retinal outer-segment membrane protein 1 ( 6-8 ).Conversely, the etiology of AMD, which is the leading cause of blindness over the age of 65, is not as clear as that of RP. AMD is also a heterogeneous group of disorders, but the causes are proposed to be multifactorial, and the main known risk factors are both genetic and environmental ( 2, 5 ). There are two forms of AMD: the dry and the wet form. In the dry form, photoreceptors degenerate slowly

The integrity of the retinal pigment epithelial (RPE) cell is essential for the survival of rod and cone photoreceptor cells. Several stressors, including reactive oxygen species, trigger apoptotic damage in RPE cells preceded by an anti-inflammatory, pro-survival response, the formation of neuroprotectin D1 (NPD1), an oxygenation product derived from the essential omega-3 fatty acid family member docosahexaenoic acid. To define the ability of NPD1 and other endogenous novel lipid mediators in cell survival, we generated a stable knockdown human RPE (ARPE-19) cell line using short hairpin RNA to target 15-lipoxygenase-1. The 15-lipoxygenase-1-deficient cells exhibited 30% of the protein expression, and 15-lipoxygenase-2 remained unchanged, as compared with an ARPE-19 cell line control established using nonspecific short hairpin RNA transfected cells. NPD1 synthesis was stimulated by tumor necrosis factor ␣/H 2 O 2 -mediated oxidative stress in nonspecific cells (controls), whereas in silenced cells, negligible amounts of NPD1, 12(S)-and 15(S)-hydroxyeicosatetraenoic acid, and lipoxin A 4 were found under these conditions. Neither control nor the deficient cells showed an increase in 15-lipoxygenase-1 protein content after 16 h of oxidative stress, suggesting that the increased activity of 15-lipoxygenase-1 is due to activation of pre-existing proteins. 15-Lipoxygenase-silenced cells also displayed an exacerbated sensitivity to oxidative stress-induced apoptosis when compared with the control cells. NPD1 selectively and potently rescued 15-lipoxygenase-silenced cells from oxidative stress-induced apoptosis. These results demonstrate that 15-lipoxygenase-1 is activated by oxidative stress in ARPE-19 cells and that NPD1 is part of an early survival signaling in RPE cells. Retinal pigment epithelial (RPE)2 cells are essential for the survival of rod and cone photoreceptors. RPE cells mediate the renewal of photoreceptor outer segments (1, 2); synthesis and secretion of neurotrophins (3); recycling of bleached visual pigments; and transport of vitamin A (4), docosahexaenoic acid (DHA), and other nutrients, and ions and fluids between photoreceptors and the choriocapillaries (5). Failure of RPE cells to accomplish their functions leads to photoreceptor damage or death and, as a consequence, decreased vision and eventually blindness. Apoptotic cell death of RPE cells takes place in retinal degenerative diseases, including retinitis pigmentosa and age-related macular degeneration; as a result, photoreceptors degenerate (6, 7).Cell fate decisions made at the ectoderm yield either neuronal progeny or RPE cells. Thus RPE cells display similarities to neuronal lineages, even when differentiated (8), that make them suitable for conversion into neurons for therapeutic purposes (9). For example, recent studies revealed mechanisms for the transdifferentiation of RPE cells that depend on the expression status of certain genes (10). These studies have created a new interest in RPE cells caused by the potential applications not on...

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