Defective cholesterol metabolism in amyotrophic lateral sclerosis.
Defective cholesterol metabolism in amyotrophic lateral sclerosis.
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DOI：
10.1194/jlr.p071639
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发表时间：
2017-01
影响因子：
6.5
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Abdel-Khalik J;Yutuc E;Crick PJ;Gustafsson JÅ;Warner M;Roman G;Talbot K;Gray E;Griffiths WJ;Turner MR;Wang Y
随着神经元死亡，胆固醇在中枢神经系统（CNS）中释放;因此，这种固醇及其代谢物可能代表神经变性的生物标志物，包括肌萎缩侧索硬化症（ALS），其中胆固醇水平的改变与预后有关。在ALS患者和健康对照的血清和脑脊液（CSF）中定量了40多种不同的甾醇。在CSF中，发现ALS样品中胆固醇浓度升高。当CSF代谢物水平标准化为胆固醇时，胆固醇代谢物3β，7 α-二羟基胆甾-5-烯-26-酸、沿着其前体3β-羟基胆甾-5-烯-26-酸和产物7α-羟基-3-氧代胆甾-4-烯-26-酸的浓度降低，而已知从循环输入CNS的代谢物在组间的浓度无差异。血清分析显示，与对照组相比，ALS患者中（25 R）26-羟基胆固醇（3β-羟基胆甾-5-烯-26-酸的直接前体）的浓度降低。我们的结论是，已知在大脑中起作用的胆汁酸生物合成的酸性分支在ALS中是有缺陷的，导致CNS无法清除过量的胆固醇，这可能对神经元细胞有毒，并伴有神经保护性3β，7 α-二羟基胆甾-5-烯-26-酸的减少。
As neurons die, cholesterol is released in the central nervous system (CNS); hence, this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS), in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF, the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalized to cholesterol, the cholesterol metabolite 3β,7α-dihydroxycholest-5-en-26-oic acid, along with its precursor 3β-hydroxycholest-5-en-26-oic acid and product 7α-hydroxy-3-oxocholest-4-en-26-oic acid, were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3β-hydroxycholest-5-en-26-oic acid, was reduced in concentration in ALS patients compared with controls. We conclude that the acidic branch of bile acid biosynthesis, known to be operative in-part in the brain, is defective in ALS, leading to a failure of the CNS to remove excess cholesterol, which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3β,7α-dihydroxycholest-5-en-26-oic acid.