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Metabolic profiling in serum, cerebrospinal fluid and brain of patients with Cerebrotendinous xanthomatosis.
Journal of Lipid Research ( IF 6.5 ) Pub Date : 2021-04-20 , DOI: 10.1016/j.jlr.2021.100078
Philip Höflinger 1 , Stefan Hauser 2 , Eylan Yutuc 3 , Holger Hengel 4 , Lauren Griffiths 3 , Florentine Radelfahr 5 , Owain W Howell 3 , Yuqin Wang 3 , Sonja L Connor 6 , P Barton Duell 7 , Andrea E DeBarber 8 , Peter Martus 9 , Dieter Lütjohann 10 , William J Griffiths 3 , Ludger Schöls 2
Affiliation  

Cerebrotendinous xanthomatosis (CTX) is caused by autosomal recessive loss-of-function mutations in CYP27A1, a gene encoding cytochrome p450 oxidase essential for bile acid synthesis, resulting in altered bile acid and lipid metabolism. Here, we aimed to identify metabolic aberrations that drive ongoing neurodegeneration in some patients with CTX despite chenodeoxycholic acid (CDCA) supplementation, the standard treatment in CTX. Using chromatographic separation techniques coupled to mass spectrometry, we analyzed 26 sterol metabolites in serum and CSF of patients with CTX and in one CTX brain. Comparing samples of drug naive patients to patients treated with CDCA and healthy controls, we identified 7α,12α-dihydroxycholest-4-en-3-one as the most prominently elevated metabolite in serum and CSF of drug naive patients. CDCA treatment substantially reduced or even normalized levels of all metabolites increased in untreated patients with CTX. Independent of CDCA treatment, metabolites of the 27-hydroxylation pathway were nearly absent in all patients with CTX. 27-hydroxylated metabolites accounted for ∼45% of total free sterol content in CSF of healthy controls but <2% in patients with CTX. Metabolic changes in brain tissue corresponded well with findings in CSF. Interestingly, 7α,12α-dihydroxycholest-4-en-3-one and 5α-cholestanol did not exert toxicity in neuronal cell culture. In conclusion, we propose that increased 7α,12α-dihydroxycholest-4-en-3-one and lack of 27-hydroxycholesterol may be highly sensitive metabolic biomarkers of CTX. As CDCA cannot reliably prevent disease progression despite reduction of most accumulated metabolites, supplementation of 27-hydroxylated bile acid intermediates or replacement of CYP27A1 might be required to counter neurodegeneration in patients with progressive disease despite CDCA treatment.

中文翻译:

脑腱黄色瘤病患者血清、脑脊液和脑中的代谢谱分析。

脑腱黄色瘤病 (CTX) 是由 CYP27A1 的常染色体隐性功能缺失突变引起的,CYP27A1 是一种编码胆汁酸合成所必需的细胞色素 p450 氧化酶的基因,导致胆汁酸和脂质代谢改变。在这里,我们旨在确定尽管鹅去氧胆酸 (CDCA) 补充剂是 CTX 的标准治疗,但仍会导致一些 CTX 患者持续神经退行性变的代谢异常。使用与质谱联用的色谱分离技术,我们分析了 CTX 患者和一个 CTX 大脑中血清和脑脊液中的 26 种甾醇代谢物。将初治患者的样本与接受 CDCA 治疗的患者和健康对照组进行比较,我们发现 7α,12α-dihydroxycholest-4-en-3-one 是初治患者血清和脑脊液中最显着升高的代谢物。在未经治疗的 CTX 患者中,CDCA 治疗显着降低或什至使所有代谢物的水平正常化。独立于 CDCA 治疗,所有 CTX 患者几乎不存在 27-羟基化途径的代谢物。27-羟基化代谢物占健康对照组脑脊液中总游离甾醇含量的 45%,但在 CTX 患者中占不到 2%。脑组织的代谢变化与脑脊液中的发现非常吻合。有趣的是,7α,12α-dihydroxycholest-4-en-3-one 和 5α-cholestanol 在神经元细胞培养中没有毒性。总之,我们提出增加的 7α,12α-dihydroxycholest-4-en-3-one 和缺乏 27-羟基胆固醇可能是 CTX 的高度敏感的代谢生物标志物。尽管大多数积累的代谢物减少,CDCA 仍不能可靠地预防疾病进展,
更新日期:2021-04-25
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