Lysosomal acid lipase (LAL), encoded by the gene LIPA, facilitates the intracellular processing of lipids by hydrolyzing cholesteryl esters and triacylglycerols present in newly internalized lipoproteins. Loss-of-function mutations in LIPA result in cholesteryl ester storage disease (CESD) or Wolman disease when mutations cause complete loss of LAL activity. Although the phenotype of a mouse CESD model has been extensively characterized, there has not been a focus on the brain at different stages of disease progression. In the current studies, whole-brain mass and the concentrations of cholesterol in both the esterified (EC) and unesterified (UC) fractions were measured in Lal^−/− and matching Lal^+/+ mice (FVB-N strain) at ages ranging from 14 up to 280 days after birth. Compared to Lal^+/+controls at 50, 68–76, 140–142, and 230–280 days of age, Lal^−/− mice had brain weights that averaged approximately 6%, 7%, 18%, and 20% less, respectively. Brain EC levels were higher in the Lal^−/− mice at every age, being elevated 27-fold at 230–280 days. Brain UC concentrations did not show a genotypic difference at any age. The elevated brain EC levels in the Lal^−/− mice did not reflect EC in residual blood. An mRNA expression analysis for an array of genes involved in the synthesis, catabolism, storage, and transport of cholesterol in the brains of 141-day old mice did not detect any genotypic differences although the relative mRNA levels for several markers of inflammation were moderately elevated in the Lal^−/− mice. The possible sites of EC accretion in the central nervous system are discussed.

中文翻译：

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尽管胆固醇酯贮积病小鼠模型的脑质量较小，但脑胆固醇稳态的分子标记物没有变化

由LIPA基因编码的溶酶体酸性脂肪酶 (LAL)通过水解新内化脂蛋白中存在的胆固醇酯和甘油三酯，促进脂质的细胞内加工。当突变导致 LAL 活性完全丧失时， LIPA中的功能丧失突变会导致胆固醇酯贮积病 (CESD) 或沃尔曼病。尽管小鼠 CESD 模型的表型已得到广泛表征，但尚未关注处于疾病进展不同阶段的大脑。在目前的研究中，全脑质量和酯化 (EC) 和未酯化 (UC) 级分中的胆固醇浓度以Lal ^-/-和匹配的Lal ^+/+测量出生后 14 至 280 天的小鼠（FVB-N 株）。与50、68–76、140–142 和 230–280 天龄的Lal ^+/+对照相比， Lal ^-/-小鼠的脑重量平均减少约 6%、7%、18% 和 20% ， 分别。Lal ^-/-小鼠的大脑 EC 水平在每个年龄段都更高，在 230-280 天时升高 27 倍。脑 UC 浓度在任何年龄都没有显示基因型差异。Lal中脑 EC 水平升高^-/-小鼠未反映残血中的EC。对参与 141 天大小鼠大脑中胆固醇合成、分解代谢、储存和运输的一系列基因的 mRNA 表达分析未检测到任何基因型差异，尽管几种炎症标志物的相对 mRNA 水平适度升高在Lal ^-/-小鼠中。讨论了中枢神经系统中 EC 增生的可能部位。