Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord.
Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord.
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DOI：
10.1038/s41598-017-02638-8
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发表时间：
2017-06-02
影响因子：
4.6
通讯作者：
Pekovic S
中科院分区：
文献类型：
--
作者：
Lavrnja I;Smiljanic K;Savic D;Mladenovic-Djordjevic A;Tesovic K;Kanazir S;Pekovic S
越来越多的证据表明，胆固醇代谢失调可能是多发性硬化症(MS)进展的一个关键事件。采用实验性自身免疫性脑脊髓炎(EAE)大鼠模型，观察了大鼠脊髓内维持胆固醇稳态的关键分子3-羟基-3-甲基戊二酰辅酶-A还原酶(HMGCR)、载脂蛋白E(ApoE)和胆固醇24-羟基酶(CYP46A1)在病程中的表达变化。脱髓鞘部位的髓鞘脂碎屑仅在EAE高峰期出现，在恢复期被有效清除。由于CYP46A1负责清除多余的胆固醇，我们对CYP46A1的表达进行了详细的分析，并揭示了其分布的区域和时间特异性。双重免疫荧光染色显示，细胞色素P46A1定位于神经元、浸润性巨噬细胞、小胶质细胞和星形胶质细胞的脱髓鞘区域，提示这些细胞在EAE的胆固醇代谢中起作用。我们认为，在EAE发病初期和高峰时胆固醇代谢调节的改变可能会增加疾病的进展，而在恢复期可能对髓鞘的再生和神经元功能的恢复有有益的影响。
Increased evidence suggests that dysregulation of cholesterol metabolism may be a key event contributing to progression of multiple sclerosis (MS). Using an experimental autoimmune encephalomyelitis (EAE) model of MS we revealed specific changes in the mRNA and protein expression of key molecules involved in the maintaining of cholesterol homeostasis in the rat spinal cord: 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46A1) during the course of disease. The presence of myelin lipid debris was seen only at the peak of EAE in demyelination loci being efficiently removed during the recovery period. Since CYP46A1 is responsible for removal of cholesterol excess, we performed a detailed profiling of CYP46A1 expression and revealed regional and temporal specificities in its distribution. Double immunofluorescence staining demonstrated CYP46A1 localization with neurons, infiltrated macrophages, microglia and astrocytes in the areas of demyelination, suggesting that these cells play a role in cholesterol turnover in EAE. We propose that alterations in the regulation of cholesterol metabolism at the onset and peak of EAE may add to the progression of disease, while during the recovery period may have beneficial effects contributing to the regeneration of myelin sheath and restoration of neuronal function.