Abstract
Abstract: :
Purpose: We previously reported (Vaughan et al, ARVO, 2003) that systemic injections of cholesterol, with or without fat–soluble vitamin supplementation, do not ameliorate or prevent retinal degeneration in a rat model of Smith–Lemli–Opitz Syndrome (SLOS). SLOS is an autosomal recessive disease caused by defective cholesterol biosynthesis, resulting in abnormally low levels of cholesterol (Chol) and excessive levels of 7–dehydrocholesterol (7DHC) in all tissues. In the present study, we evaluate the ability of a high–Chol diet to rescue visual function, retard/prevent retinal degeneration, and normalize retinal sterol composition, relative to rats receiving a Chol–free diet. Methods: Pregnant Sprague–Dawley rats (6 days sperm–positive) were fed 0% Chol chow and administered AY9944 (an inhibitor of the defective enzyme in SLOS; 0.37 mg/kg/day) by Alzet pump (Fliesler et al., ARVO, 2003). Their progeny were injected 3X per wk with AY9944 (30 mg/kg; Fliesler et al., IOVS 40:1792, 1999). At weaning, litters were divided into parallel dietary treatment groups (0% vs. 2% Chol chow, N=12 each). Control dams received 0% chol chow, but no drug; control progeny were injected with vehicle per same regimen. At 3 mo. postnatal, dark– and light–adapted ERGs were recorded; one retina was taken for quantitative morphometric analysis; and the contralateral retina – plus serum, liver, and brain – were harvested for sterol analysis. Results: Retina 7DHC/Chol mole ratio values were 5.00±0.38 (0% Chol) vs. 1.60±0.08 (2% Chol), largely due to a 2.4–fold increase in [Chol], rather than the modest (23%) reduction in [7DHC] upon Chol feeding, with no difference in total sterol content. Control retinas had essentially no 7DHC, and their total sterol content was ca. 12% greater than in either treatment group. Rod and cone function were markedly compromised (decreased amplitudes, increased implicit times), relative to controls, in both feeding groups, but the 2% Chol group showed improved function relative to the 0% Chol group. Mean outer nuclear layer (ONL) thickness was reduced, relative to controls, in the 0% Chol group, but not in the 2% Chol group. However, mean rod outer segment (ROS) length was reduced in both treatment groups, relative to controls. Conclusions:A high–Chol diet has a partial sparing effect on photoreceptor function and viability in this SLOS animal model, but does not spare ROS loss.
Keywords: lipids • retinal degenerations: cell biology • photoreceptors