Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients.
Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients.
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DOI：
10.1007/s12035-016-0281-9
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发表时间：
2017-12
影响因子：
5.1
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Crick PJ;Griffiths WJ;Zhang J;Beibel M;Abdel-Khalik J;Kuhle J;Sailer AW;Wang Y
多发性硬化症(MS)是一种中枢神经系统(CNS)的自身免疫性炎症性疾病。我们测定了MS、炎症性中枢神经系统疾病、神经退行性疾病患者和正常对照组血浆和脑脊液中20多种非酯化类固醇的水平。采用多级裂解(MS N)技术，采用液质联用(LC-MS)进行酶辅助衍生化后的分析。我们发现，在每种疾病状态下，脑脊液中胆汁酸前体的浓度都增加了，被归类为疑似自身免疫性疾病或病因不明的炎症性中枢神经系统疾病的患者脑脊液中25-羟基胆固醇(25-HC，P<0.05)的浓度也升高。脑脊液中的胆固醇浓度没有变化，除了被诊断为肌萎缩侧索硬化症(P<0.01)或病原体引起的中枢神经系统感染(P<0.05)的患者。在血浆中，我们发现复发-缓解期MS患者血浆25-HC(P<0.01)、(25R)26-羟基胆固醇((25R)26-HC，P<0.05)和7-羟基-3-氧胆烷-4-烯酸(7α-αH，3O-CA，P<0.05)较对照组降低。血浆25-HC、(25R)26-HC和7-αH，3O-CA水平的降低是RRMS所特有的。综上所述，我们发现RRMS患者血浆中25-HC浓度显著低于对照组。这与以下假设是一致的，即巨噬细胞合成25-HC的倾向降低将导致25-HC对IL-1家族细胞因子产生的负反馈减少，并加剧脑脊液中的MS。我们发现，在脑脊液中，主要代谢产物反映了胆汁酸生物合成的酸性途径，在中枢神经系统疾病中，这些代谢产物的水平升高可能反映了脱髓鞘或神经元死亡导致的胆固醇释放。在炎症性中枢神经系统疾病患者中，25-HC升高可能是由于1型干扰素刺激基因-巨噬细胞胆固醇25-羟基酶上调所致。本文的在线版本(doi：10.1007/s12035-0160281-9)包含补充材料，授权用户可以使用。
Multiple sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system (CNS). We have measured the levels of over 20 non-esterified sterols in plasma and cerebrospinal fluid (CSF) from patients suffering from MS, inflammatory CNS disease, neurodegenerative disease and control patients. Analysis was performed following enzyme-assisted derivatisation by liquid chromatography–mass spectrometry (LC–MS) exploiting multistage fragmentation (MS n). We found increased concentrations of bile acid precursors in CSF from each of the disease states and that patients with inflammatory CNS disease classified as suspected autoimmune disease or of unknown aetiology also showed elevated concentrations of 25-hydroxycholestertol (25-HC, P < 0.05) in CSF. Cholesterol concentrations in CSF were not changed except for patients diagnosed with amyotrophic lateral sclerosis (P < 0.01) or pathogen-based infections of the CNS (P < 0.05) where they were elevated. In plasma, we found that 25-HC (P < 0.01), (25R)26-hydroxycholesterol ((25R)26-HC, P < 0.05) and 7α-hydroxy-3-oxocholest-4-enoic acid (7αH,3O-CA, P < 0.05) were reduced in relapsing-remitting MS (RRMS) patients compared to controls. The pattern of reduced plasma levels of 25-HC, (25R)26-HC and 7αH,3O-CA was unique to RRMS. In summary, in plasma, we find that the concentration of 25-HC in RRMS patients is significantly lower than in controls. This is consistent with the hypothesis that a lower propensity of macrophages to synthesise 25-HC will result in reduced negative feedback by 25-HC on IL-1 family cytokine production and exacerbated MS. In CSF, we find that the dominating metabolites reflect the acidic pathway of bile acid biosynthesis and the elevated levels of these in CNS disease is likely to reflect cholesterol release as a result of demyelination or neuronal death. 25-HC is elevated in patients with inflammatory CNS disease probably as a consequence of up-regulation of the type 1 interferon-stimulated gene cholesterol 25-hydroxylase in macrophages. The online version of this article (doi:10.1007/s12035-016-0281-9) contains supplementary material, which is available to authorized users.
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影响因子：
32.4
作者：
Blanc M;Hsieh WY;Robertson KA;Kropp KA;Forster T;Shui G;Lacaze P;Watterson S;Griffiths SJ;Spann NJ;Meljon A;Talbot S;Krishnan K;Covey DF;Wenk MR;Craigon M;Ruzsics Z;Haas J;Angulo A;Griffiths WJ;Glass CK;Wang Y;Ghazal P
通讯作者：
Ghazal P
DOI：
10.1073/pnas.0909142106
发表时间：
2009-09-29
影响因子：
11.1
作者：
Bauman, David R.;Bitmansour, Andrew D.;Russell, David W.
通讯作者：
Russell, David W.
影响因子：
9.9
作者：
Kasper, Lloyd H.;Shoemaker, Jennifer
通讯作者：
Shoemaker, Jennifer
影响因子：
6.4
作者：
Lassmann, Hans;Brueck, Wolfgang;Lucchinetti, Claudia F.
通讯作者：
Lucchinetti, Claudia F.
影响因子：
4.8
作者：
Brown, J;Theisler, C;Wolozin, B
通讯作者：
Wolozin, B