FEEDBACK-REGULATION OF 3-HYDROXY-3-METHYGLUTARYL COENZYME A REDUCTASE IN LIVERS OF MICE TREATED WITH MEVINOLIN, A COMPETITIVE INHIBITOR OF THE REDUCTASE
FEEDBACK-REGULATION OF 3-HYDROXY-3-METHYGLUTARYL COENZYME A REDUCTASE IN LIVERS OF MICE TREATED WITH MEVINOLIN, A COMPETITIVE INHIBITOR OF THE REDUCTASE
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DOI：
10.1172/jci109938
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发表时间：
1980-01-01
影响因子：
15.9
通讯作者：
GOLDSTEIN, JL
中科院分区：
文献类型：
--
作者：
KITA, T;BROWN, MS;GOLDSTEIN, JL
美伐他汀（ML-236 B）和相关化合物美维诺林是3-羟基-3-甲基戊二酰辅酶A还原酶（HMG CoA还原酶）的竞争性抑制剂，该酶是胆固醇合成中的速率控制酶。对培养的细胞施用康帕汀引起细胞中HMG CoA还原酶的量的补偿性增加。据报道，在用制甲羟氨苄青霉素治疗的大鼠和小鼠的肝脏中，HMG CoA还原酶也有类似的增加。在喂食对照饲料和2%胆固醇饲料的小鼠中，研究了mevinolin介导的肝脏HMG CoA还原酶增加的机制。给予对照饮食的小鼠mevinolin使肝微粒体中HMG CoA还原酶的量增加6至10倍。当小鼠被喂食富含胆固醇的饮食时，胆固醇在肝脏中积累，HMG CoA还原酶下降了90%。给予胆固醇喂养的小鼠mevinolin使HMG CoA还原酶增加3至8倍。尽管mevinolin处理的胆固醇喂养动物的肝脏中已经存在大量的胆固醇，但它们升高的HMG CoA还原酶可被s.c.注射少量甲羟戊酸，HMG CoA还原酶的产物。这些数据是兼容的HMG CoA还原酶，其中抑制酶需要从甲羟戊酸衍生的甾醇和非甾醇物质的多价反馈调节机制在小鼠肝脏中的存在。通过阻断甲羟戊酸合成，mevinolin激活了这种调节机制，这反过来又导致肝脏HMG CoA还原酶增加。用甲羟戊酸抑制升高的HMG CoA还原酶的能力可用于增强mevinolin作为降胆固醇剂的有效性。
Compactin (ML-236B) and the related compound, mevinolin, are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate-controlling enzyme in cholesterol synthesis. Administration of compactin to cultured cells elicits a compensatory increase in the amount of HMG CoA reductase in the cells. A similar increase in HMG CoA reductase was reported in livers of rats and mice treated with compactin. The mechanism for the mevinolin-mediated increase in hepatic HMG CoA reductase in mice that were fed a control diet and a 2% cholesterol diet was studied. Administration of mevinolin to mice on a control diet produced a 6- to 10-fold increase in the amount of HMG CoA reductase in liver microsomes. When mice were fed the cholesterol-enriched diet, cholesterol accumulated in the liver and HMG CoA reductase declined by 90%. The administration of mevinolin to cholesterol-fed mice produced a 3- to 8-fold increase in HMG CoA reductase. Despite the abundant amount of cholesterol that was already present in the livers of the mevinolin-treated, cholesterol-fed animals, their elevated HMG CoA reductase could be rapidly suppressed by the s.c. injection of small amounts of mevalonate, the product of HMG CoA reductase. The data are compatible with the existence in mouse liver of a multivalent feedback regulatory mechanism for HMG CoA reductase in which suppression of the enzyme requires both a sterol and a nonsterol substance derived from mevalonate. By blocking mevalonate synthesis, mevinolin activates this regulatory mechanism and this in turn causes an increase in hepatic HMG CoA reductase. The ability to suppress the elevated HMG CoA reductase with mevalonate may be useful in potentiating the effectiveness of mevinolin as a hypocholesterolemic agent.