Reproducing abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome by inhibiting the conversion of 7-dehydrocholesterol to cholesterol in rats.
Reproducing abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome by inhibiting the conversion of 7-dehydrocholesterol to cholesterol in rats.
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DOI：
10.1172/jci117678
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发表时间：
1995
期刊：
影响因子：
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通讯作者：
Guorong Xu;G. Salen;S. Shefer;Gene C. Ness;Thomas S. Chen;Zhihong Zhao;G. Tint
中科院分区：
文献类型：
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作者：
Guorong Xu;G. Salen;S. Shefer;Gene C. Ness;Thomas S. Chen;Zhihong Zhao;G. Tint
Smith-Lemli-Opitz综合征是一种以神经发育缺陷和许多器官畸形为特征的隐性遗传疾病。最近，在纯合子中发现了伴随7-脱氢胆固醇向胆固醇转化受损的异常胆固醇生物合成。为了重现生化异常，将7-脱氢胆固醇- δ 7-还原酶（催化7-脱氢胆固醇转化为胆固醇的酶）的竞争性抑制剂bm15.766灌胃给大鼠。14 d后，血浆胆固醇浓度从48 mg/dl下降到16 mg/dl， 7-脱氢胆固醇水平从微量上升到17 mg/dl。中心静脉周围的肝细胞出现球囊性坏死。与单独使用抑制剂相比，用胆胺刺激胆固醇合成后再用bm15.766，血浆胆固醇水平下降40% (P < 0.05)， 7-脱氢胆固醇水平增加34%。在bm15.766治疗的第2周，饲粮中添加2%的胆固醇使血浆胆固醇升高3倍，7-脱氢胆固醇浓度降低55%。肝脏3-羟基-3-甲基戊二酰辅酶A （HMG-CoA）还原酶活性升高73%，mRNA水平升高3.9倍，但胆固醇7 -羟化酶活性略有下降，mRNA水平升高1.4倍。这些结果表明bm15.766是一种有效的7-脱氢胆固醇- δ 7还原酶抑制剂。该模型再现了在Smith-Lemli-Opitz综合征中看到的异常胆固醇生物合成，并可用于测试不同的治疗策略。刺激胆固醇合成的早期步骤加重了生化异常，而喂养胆固醇抑制异常合成，改善生化异常，防止肝损伤。
The Smith-Lemli-Opitz syndrome is a recessive inherited disorder characterized by neurologic developmental defects and dysmorphic features in many organs. Recently, abnormal cholesterol biosynthesis with impaired conversion of 7-dehydrocholesterol to cholesterol has been discovered in homozygotes. To reproduce the biochemical abnormality, BM 15.766, a competitive inhibitor of 7-dehydrocholesterol-delta 7-reductase, the enzyme that catalyzes the conversion of 7-dehydrocholesterol into cholesterol was fed by gavage to rats. After 14 d, plasma cholesterol concentrations declined from 48 mg/dl to 16 mg/dl and 7-dehydro-cholesterol levels rose from trace to 17 mg/dl. Hepatocytes surrounding the central vein developed balloon necrosis. Stimulating cholesterol synthesis with cholestyramine followed by BM 15.766 produced an additional 40% decline (P < 0.05) in plasma cholesterol and 34% increase in 7-dehydrocholesterol levels compared to the inhibitor alone. Adding 2% cholesterol to the diet during the second week of BM 15.766 treatment increased plasma cholesterol threefold and decreased 7-dehydrocholesterol concentrations 55%. Hepatic 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase activity increased 73% with a 3.9-fold rise in mRNA levels but cholesterol 7 alpha-hydroxylase activity decreased slightly though mRNA levels increased 1.4 times with BM 15.766 treatment. These results demonstrate that BM 15.766 is a potent inhibitor of 7-dehydrocholesterol-delta 7-reductase. The model reproduces abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome and is useful to test different treatment strategies. Stimulating early steps of cholesterol synthesis worsens the biochemical abnormalities while feeding cholesterol inhibits abnormal synthesis, improves the biochemical abnormalities and prevents liver damage.