The role of retinyl ester hydrolases in the visual cycle

Vitamin A (including the derivates retinal, retinol, and retinyl esters) is crucial for maintaining vision in mammals. During the visual process, absorption of light leads to the isomerization of 11-cis retinal to all-trans retinal. To maintain vision, all-trans retinal needs to be converted back to 11-cis retinal through a chain of biochemical reactions, a process termed the visual cycle. A crucial reaction during the visual cycle is the conversion of retinol to retinyl esters. These retinyl esters are stored in lipid- droplet-like structures, so called retinosomes, of retinal pigment epithelial (RPE) cells. Impaired generation of retinyl esters in RPE cells has been shown to drastically impair 11-cis retinal recycling and vision in mice. This observation implies that not only the generation but also the breakdown of retinyl esters is crucial for 11-cis retinal recycling in RPE cells. The breakdown of retinyl esters is facilitated by enzymes called retinyl ester hydrolases. However, to date little is known about the identity and function of these retinyl ester hydrolases in the visual cycle. Our preliminary experiments indicate, that retinyl ester hydrolases such as adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and KIAA1363 contribute to retinyl ester breakdown in RPE cells. In this project, we hypothesize that the degradation of retinyl esters requires the action of retinyl ester hydrolases such as ATGL, HSL, and KIAA1363, for maintaining the visual cycle. Thus, impairments in retinyl ester degradation in respective enzyme-deficient mouse models are expected to affect 11-cis retinal recycling in RPE cells and therefore compromise visual function. We aim to identify and characterize a so far unknown mechanism by which retinyl esters are degraded within retinosomes of RPE cells to maintain the visual cycle. The outcome of this basic research project will shed light on a yet unexplored aspect of the visual cycle and may reveal new strategies or targets for the treatment of visual impairments.