German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany.
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
J Lipid Res. 2021;62:100078. doi: 10.1016/j.jlr.2021.100078. Epub 2021 Apr 20.
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 cerebrospinal fluid (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.
脑腱黄瘤病（CTX）是由 CYP27A1 的常染色体隐性功能丧失突变引起的，CYP27A1 基因编码细胞色素 p450 氧化酶，对于胆汁酸合成至关重要，导致胆汁酸和脂质代谢异常。在这里，我们旨在确定代谢异常，这些异常导致尽管补充鹅脱氧胆酸（CDCA），CTX 的标准治疗，但仍在一些 CTX 患者中导致进行性神经退行性变。我们使用色谱分离技术与质谱法相结合，分析了 CTX 患者的血清和脑脊液（CSF）中的 26 种甾醇代谢物，以及 1 例 CTX 脑。将未用药的患者样本与用 CDCA 治疗的患者和健康对照组进行比较，我们确定 7α,12α-二羟胆甾-4-烯-3-酮是未用药患者血清和 CSF 中升高最明显的代谢物。CDCA 治疗可显著降低或甚至使未经治疗的 CTX 患者中所有升高的代谢物水平正常化。独立于 CDCA 治疗，所有 CTX 患者的 27-羟化途径代谢物几乎不存在。27-羟化代谢物占健康对照组 CSF 中总游离甾醇含量的约 45％，但在 CTX 患者中<2％。脑组织中的代谢变化与 CSF 中的发现非常吻合。有趣的是，7α,12α-二羟胆甾-4-烯-3-酮和 5α-胆甾醇在神经元细胞培养中没有毒性。总之，我们提出，7α,12α-二羟胆甾-4-烯-3-酮的增加和 27-羟胆固醇的缺乏可能是 CTX 的高度敏感代谢生物标志物。由于尽管降低了大多数积累的代谢物，CDCA 仍不能可靠地预防疾病进展，因此可能需要补充 27-羟化胆汁酸中间产物或替代 CYP27A1，以抵消尽管进行 CDCA 治疗但仍有进行性疾病的患者的神经退行性变。
