Honda A, Salen G, Matsuzaki Y, Batta A K, Xu G, Leitersdorf E, Tint G S, Erickson S K, Tanaka N, Shefer S
Department of Gastroenterology, University of Tsukuba, Tsukuba City 305-8575, Japan.
J Lipid Res. 2001 Feb;42(2):291-300.
Cerebrotendinous xanthomatosis (CTX) is a rare, recessively inherited lipid storage disease characterized by a markedly reduced production of chenodeoxycholic acid and an increased formation of 25-hydroxylated bile alcohols and cholestanol. Patients with this disease are known to have mutations in the sterol 27-hydroxylase (Cyp27) gene. However, one study showed that mice with a disrupted Cyp27 gene did not have any CTX-related clinical or biochemical abnormalities. To explore the reason, hepatic cholesterol, cholestanol, and 12 intermediates in bile acid biosynthetic pathways were quantified in 10 Cyp27(-/-) and 7 Cyp27(+/+) mice, two CTX patients (untreated and treated with chenodeoxycholic acid), and four human control subjects by high resolution gas chromatography-mass spectrometry. Mitochondrial 27-hydroxycholesterol and 5beta-cholestane-3alpha,7alpha,12alpha,27-tetrol were virtually absent in both Cyp27(-/-) mice and CTX patients. In Cyp27(-/-) mice, microsomal concentrations of intermediates in the early bile acid biosynthetic pathway (7alpha-hydroxycholesterol, 7alpha-hydroxy-4-cholesten-3-one, 7alpha,12alpha-dihydroxy-4-cholesten-3-one, and 5beta-cholestane-3alpha,7alpha,12alpha-triol), 25-hydroxylated bile alcohols (5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol, 5beta-cholestane-3alpha,7alpha,12alpha,23R,25-pentol, and 5beta-cholestane-3alpha,7alpha,12alpha,24R, 25-pentol), and cholestanol were all significantly elevated compared with those in Cyp27(+/+) mice, although the levels were lower than those in untreated CTX patients. The intermediate levels in early bile acid biosynthesis were more elevated in male (16;-86% of CTX) than in female Cyp27(-/-) mice (7-30% of CTX). In contrast, 25-hydroxylated bile alcohol concentrations were not significantly different between male and female Cyp27(-/-) mice and were considerably lower (less than 14%) than those in CTX patients.These results suggest that 1) in Cyp27(-/-) mice, especially in females, classic bile acid biosynthesis via 7alpha-hydroxycholesterol is not stimulated as much as in CTX patients; and 2) formed 25-hydroxylated bile alcohols are more efficiently metabolized in Cyp27(-/-) mice than in CTX patients.
脑腱黄瘤病（CTX）是一种罕见的隐性遗传脂质贮积病，其特征是鹅去氧胆酸的生成显著减少，25-羟基胆汁醇和胆甾烷醇的生成增加。已知患有这种疾病的患者在甾醇27-羟化酶（Cyp27）基因中有突变。然而，一项研究表明，Cyp27基因被破坏的小鼠没有任何与CTX相关的临床或生化异常。为了探究原因，通过高分辨率气相色谱-质谱法对10只Cyp27（-/-）小鼠、7只Cyp27（+/+）小鼠、两名CTX患者（未治疗和用鹅去氧胆酸治疗）以及四名人类对照受试者的肝脏胆固醇、胆甾烷醇和胆汁酸生物合成途径中的12种中间体进行了定量分析。在Cyp27（-/-）小鼠和CTX患者中，线粒体27-羟基胆固醇和5β-胆甾烷-3α，7α，12α，27-四醇实际上均不存在。在Cyp27（-/-）小鼠中，胆汁酸生物合成早期途径中的中间体（7α-羟基胆固醇、7α-羟基-4-胆甾烯-3-酮、7α，12α-二羟基-4-胆甾烯-3-酮和5β-胆甾烷-3α，7α，12α-三醇）、25-羟基胆汁醇（5β-胆甾烷-3α，7α，12α，25-四醇、5β-胆甾烷-3α，7α，12α，23R，25-五醇和5β-胆甾烷-3α，7α，12α，24R，25-五醇）以及胆甾烷醇的微粒体浓度均比Cyp27（+/+）小鼠显著升高，尽管其水平低于未治疗的CTX患者。雄性Cyp27（-/-）小鼠（为CTX患者的16%-86%）早期胆汁酸生物合成中的中间体水平比雌性Cyp27（-/-）小鼠（为CTX患者的7%-30%）升高得更多。相比之下，雄性和雌性Cyp27（-/-）小鼠之间2�-羟基胆汁醇浓度没有显著差异，且比CTX患者的浓度低得多（低于14%）。这些结果表明：1）在Cyp27（-/-）小鼠中，尤其是雌性小鼠，经由7α-羟基胆固醇的经典胆汁酸生物合成没有像在CTX患者中那样受到强烈刺激；2）生成的25-羟基胆汁醇在Cyp27（-/-）小鼠中比在CTX患者中代谢得更有效。
