Investigation of pathogenesis of CNS lesions in patients with peroxisome biogenesis disorders

本研究旨在探讨过氧酶体生物发生障碍时脂类组成和代谢的变化。在ZS患者的大脑皮质中，神经酰胺单己糖苷(CMH)和胆固醇酯(CE)的含量与不同年龄的对照组相比有所增加。虽然CMH在白质中随年龄增长而积累，但在ZS中并未发现CMH增加。PC+PS组分的分子种类分析显示，ZS大脑皮层中的二棕榈酰甘油磷脂含量显著增加。我们还分析了ZP102细胞中的脂质成分，发现了过氧酶体缺陷、脂肪酸的β氧化和血浆蛋白原的生物合成受损。ZP102细胞中游离脂肪酸的浓度是CHO-K1细胞的两倍，但其甲酯和三酰甘油的含量低于对照细胞。ZP102细胞中CMH的浓度显著高于对照细胞，且两种细胞间的脂肪酸分子种类，特别是饱和与不饱和脂肪酸的比例有所不同。ZP102细胞对神经鞘磷脂(SM)和CMH的掺入速率高于CHO-K1细胞。从培养上清液中去除甘油酸后24小时，加入细胞的甘油酸主要用于SM的合成。ZP102细胞的膜迁移率低于CHO-K1细胞。脂代谢的改变，特别是饱和脂肪酸和鞘磷脂代谢的增强，可能与ZP102细胞膜流动性降低有关，这与PBD的膜连接过程功能障碍有关。

The study was conducted to determine the changes in the compositions and metabolism of lipids in peroxisome biogenesis disorders. In the cerebral cortex of a ZS patient, the amounts of ceramide monohexoside (CMH) and cholesterol ester (CE) increased in comparison to control levels of various ages. Although CMH accumulated with age in the white matter, absence of increase of CMH was recognized in ZS. Analysis of molecular species of PC plus PS fraction revealed significant increase of dipalmytoyl glycerophospholipids in cerebral cortex of ZS. We also analyzed lipids composition in ZP102 cells defect peroxisomes and exhibit impairments of peroxisomal β-oxidation of fatty acids and biosynthesis of plasmalogen. The concentration of free fatty acids in ZP102 cells was twice that in CHO-K1 cells, but their methyl esters and triacylglycerol in ZP102 cells were decreased in comparison to the control cells. Also, the concentration of CMH in ZP102 cells was significantly increased compared to that in the control cells, and the fatty acid molecular species, particularly the ratio of saturated and unsaturated ones, of individual lipids were different between two cell types. The rate of incorporation of [^<14>C] labeled saturated acids into sphingomyelin (SM) and CMH in ZP102 cells was higher than that in CHO-K1 cells. Lignoceric acid incorporated into cells was dominantly utilized for the synthesis of SM at 24 hr after removal of [^<14>C] lignoceric acid from the culture medium. ZP102 cells showed lower membrane mobility as compared to CHO-K1 cells. Alteration of lipid metabolism in particular enhanced metabolism of saturated fatty acids and sphingolipids may be related to the reduced membrane fluidity of ZP102 cells, which is implicated in dysfunction of membrane-linked processes in PBD