Cholesterol synthesis in the vertebrate retina: Effects of U18666A on rat retinal structure, photoreceptor membrane assembly, and sterol metabolism and composition

Treatment of neonatal rats with U18666A, an inhibitor of desmosterol Delta( 24)-reductase, results in accumulation of desmosterol (Delta(5,24)) and dep letion of cholesterol (Delta(5)) in various bodily tissues and also causes cataracts. We evaluated the effects of U18666A on the sterol composition, d e novo sterol synthesis, and histological structure of the retina. Neonatal Sprague-Dawley rats were injected subcutaneously with U18666A (15 mg/kg, i n olive oil) every other day from birth through 3 wk of age; in parallel, c ontrol rats received olive oil atone. At 21 d, treated and control groups e ach were subdivided into two groups: one group of each was injected intravi treally with [H-3]acetate; retinas were removed 20 h later and non-saponifi able lipids (NSL) were analyzed by radio-high-performance liquid chromatogr aphy. The other group was injected intravitreally with [H-3]leucine; 4 d la ter, one eye of each animal was evaluated by light and electron microscopy and light microscopic autoradiography, while contralateral retinas and rod outer segment (ROS) membranes prepared therefrom were analyzed by sodium do decyl sulfate-polyacrylamide gel electrophoresis/fluorography. In the treat ed group, the Delta(5)/Delta(5,24) mole ratio of retinas was ca. 1.0, and > 88% of the NSL radioactivity was in Delta(5,24); in contrast, control retin as had Delta(5)/Delta(5,24) >170, with >80% of the NSL radioactivity in Del ta(5). Retinal histology, ultrastructure, ROS renewal rates, and rhodopsin synthesis and intracellular trafficking were comparable in both treated and control animals. These results suggest that desmosterol can either substit ute functionally for cholesterol in the retina or it can complement subthre shold levels of cholesterol by sterol synergism.