Boesze-Battaglia Kathleen, Damek-Poprawa Monika, Mitchell Drake C, Greeley Laura, Brush Richard S, Anderson Robert E, Richards Michael J, Fliesler Steven J
Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Lipid Res. 2008 Jul;49(7):1488-99. doi: 10.1194/jlr.M800031-JLR200. Epub 2008 Mar 14.
Smith-Lemli-Opitz syndrome (SLOS) is caused by an inherited defect in the last step in cholesterol (Chol) biosynthesis, leading to abnormal accumulation of 7-dehydrocholesterol and decreased Chol levels. Progressive retinal degeneration occurs in an animal model of SLOS, induced by treating rats with AY9944, a selective inhibitor of the enzyme affected in SLOS. Here we evaluated alterations in the biochemical and physical properties of retinal rod outer segment (ROS) membranes in this animal model. At 1 month of AY9944 treatment, there were modest alterations in fatty acid composition, but no significant differences in cis-parinaric acid (cPA) spectroscopic parameters in ROS membranes from treated versus control rats. However, at 3 months, ROS docosahexaenoic acid (DHA) content was dramatically reduced, and cPA fluorescence anisotropy values were decreased, relative to controls. Also, 1,6-diphenyl-1,3,5-hexatriene exhibited decreased rotational motion and increased orientational order in ROS membranes from 3 month-old AY9944-treated rats, relative to controls. No significant changes in protein:lipid ratios were observed; however, rhodopsin regenerability was compromised by 3 months of treatment. These findings are consistent with reduced ROS membrane fluidity in the SLOS rat model, relative to controls, primarily due to the dramatic reduction in membrane DHA levels, rather than altered sterol composition.
史密斯-勒米-奥皮茨综合征（SLOS）是由胆固醇（Chol）生物合成最后一步的遗传性缺陷引起的，导致7-脱氢胆固醇异常蓄积和Chol水平降低。在SLOS动物模型中会发生进行性视网膜变性，该模型是通过用AY9944（一种在SLOS中受影响酶的选择性抑制剂）处理大鼠诱导产生的。在此，我们评估了该动物模型中视网膜视杆细胞外段（ROS）膜的生化和物理性质的改变。在AY9944处理1个月时，脂肪酸组成有适度改变，但处理组与对照组大鼠ROS膜中顺式-杷荏酸（cPA）光谱参数无显著差异。然而，在3个月时，相对于对照组，ROS二十二碳六烯酸（DHA）含量显著降低，且cPA荧光各向异性值下降。此外，相对于对照组，在3月龄经AY9944处理的大鼠的ROS膜中，1,6-二苯基-1,3,5-己三烯的旋转运动减少，取向有序性增加。未观察到蛋白质与脂质比率有显著变化；然而，处理3个月后视紫红质的再生能力受损。这些发现与SLOS大鼠模型中ROS膜流动性相对于对照组降低一致，主要是由于膜DHA水平显著降低，而非固醇组成改变。
