Regulation of cholesterol biosynthetic pathway in patients with the Smith-Lemli-Opitz syndrome
Regulation of cholesterol biosynthetic pathway in patients with the Smith-Lemli-Opitz syndrome
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DOI：
10.1023/a:1005660130109
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发表时间：
2000-07-01
影响因子：
4.2
通讯作者：
Tanaka, N
中科院分区：
文献类型：
--
作者：
Honda, M;Tint, GS;Tanaka, N
Smith-Lemli-Opitz综合征(SLOS)是一种隐性遗传性出生疾病，由7-脱氢胆固醇(3-β-羟基类固醇)Delta(7)-还原酶缺陷引起，该酶是胆固醇生物合成的最终酶。为了研究SLOS中胆固醇生物合成途径的体内调控，我们测定了一例SLOS患者和11例对照的肝脏微粒体中的类固醇浓度和几种关键酶的活性，包括HMG-CoA合成酶、HMG-CoA还原酶、角鲨烯合成酶和7-脱氢胆固醇Delta(7)-还原酶。患者肝微体7-脱氢胆固醇Delta(7)-还原酶活性低于对照组平均值的1%，并可见患者微体中胆固醇浓度降低，7-和8-脱氢胆固醇浓度显著升高。患者的HMG-CoA合酶和角鲨烯合酶活性分别上调到149%和532%，而该途径中的限速酶HMG-CoA还原酶的活性下降到对照平均值的39%。通过检测血浆中HMG-CoA还原酶的直接产物甲伐他酸的水平，支持下调SLOS中HMG-CoA还原酶的活性。系统性红斑狼疮患者(n=9)与年龄匹配的正常对照组(n=8)相比，其血浆IL-6水平显著降低(12+/-2vs28+/-6nmol/L，p<；0.05)。这些结果表明，在大多数SLOS患者体内，尽管胆固醇生物合成途径被阻断，血浆和肝脏胆固醇浓度降低，但HMG-CoA还原酶不被激活。
The Smith-Lemli-Opitz syndrome (SLOS) is a recessively inherited birth disorder caused by a defect in 7-dehydrocholesterol (3 beta-hydroxysteroid) Delta(7)-reductase, the final enzyme in cholesterol biosynthesis. To investigate in vivo regulation of the cholesterol biosynthetic pathway in SLOS, we measured hepatic microsomal sterol concentrations and activities of several key enzymes in the pathway, including HMG-CoA synthase, HMG-CoA reductase, squalene synthase and 7-dehydrocholesterol Delta(7)-reductase in liver specimens from a patient with SLOS and 11 controls. Hepatic microsomal 7-dehydrocholesterol Delta(7)-reductase activity in the patient was less than 1% of the control mean, and decreased cholesterol concentration and markedly increased 7- and 8-dehydrocholesterol concentrations were observed in the patient's microsomes. HMG-CoA synthase and squalene synthase activities in the patient were upregulated to 149% and 532%, respectively, while the activity of HMG-CoA reductase, the rate-limiting enzyme in the pathway, was reduced to 39% of the control mean. Downregulation of HMG-CoA reductase activity in SLOS was supported by measuring plasma levels of mevalonic acid, the immediate product of HMG-CoA reductase. The levels in SLOS patients (n=9) were significantly low compared with age-matched controls (n=8) (12 +/- 2 vs 28 +/- 6 nmol/L, p < 0.05). These results suggest that in most SLOS patients in vivo HMG-CoA reductase is not stimulated in spite of blocked cholesterol biosynthetic pathway and reduced plasma and hepatic cholesterol concentrations.