Genetic tuning of β-carotene oxygenase-1 activity rescues cone photoreceptor function in STRA6-deficient mice

Abstract

Abstract Rod and cone photoreceptors in the retina mediate dim light and daylight vision, respectively. Despite their distinctive functions, rod and cone visual pigments utilize the same vitamin A-derived chromophore. To sustain vision, vitamin A precursors must be acquired in the gut, metabolized, and distributed to the eyes. Deficiencies in this pathway in inherited ocular disease states deplete cone photoreceptors from chromophore and eventually lead to cell death, whereas the more abundant rod photoreceptors are less affected. However, pathways that support cone function and survival under such conditions are largely unknown. Using biochemical, histological, and physiological approaches, we herein show that intervention with β-carotene in STRA6-deficient mice improved chromophore supply to cone photoreceptors. Relieving the inherent negative feedback regulation of β-carotene oxygenase-1 activity in the intestine by genetic means further bolstered cone photoreceptor functioning in the STRA6-deficient eyes. A vitamin A-rich diet, however, did not improve cone photoreceptor function in STRA6-deficiency. We provide evidence that the beneficial effect of β-carotene on cones results from favorable serum kinetics of retinyl esters in lipoproteins. The respective alterations in lipoprotein metabolism maintained a steady supply of retinoids to the STRA6-deficient eyes, which ameliorated the competition for chromophore between rod and cone photoreceptors. Together, our study elucidates a cone photoreceptor-survival pathway and unravels an unexpected metabolic connection between the gut and the retina.