Kita T, Brown M S, Goldstein J L
J Clin Invest. 1980 Nov;66(5):1094-100. doi: 10.1172/JCI109938.
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. Previous studies have shown that 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 has been reported in livers of rats and mice that have been treated with compactin. In this study, we explore the mechanism for the mevinolin-mediated increase in hepatic HMG CoA reductase in mice that have been fed a control diet and a 2% cholesterol diet. 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 three to eightfold 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 subcutaneous injection of small amounts of mevalonate, the product of HMG CoA reductase. These 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 prove useful in potentiating the effectiveness of mevinolin as a hypocholesterolemic agent.
美伐他汀（ML - 236B）及相关化合物莫纳可林，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限速酶。先前的研究表明，向培养细胞中添加美伐他汀会引发细胞内HMG CoA还原酶量的代偿性增加。在用美伐他汀处理过的大鼠和小鼠肝脏中也报道了类似的HMG CoA还原酶增加情况。在本研究中，我们探究了在喂食对照饮食和2%胆固醇饮食的小鼠中，莫纳可林介导的肝脏HMG CoA还原酶增加的机制。给喂食对照饮食的小鼠施用莫纳可林，会使肝脏微粒体中HMG CoA还原酶的量增加6至10倍。当小鼠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%。给喂食胆固醇的小鼠施用莫纳可林，会使HMG CoA还原酶增加三至八倍。尽管在经莫纳可林处理且喂食胆固醇的动物肝脏中已经存在大量胆固醇，但通过皮下注射少量甲羟戊酸（HMG CoA还原酶的产物），它们升高的HMG CoA还原酶可被迅速抑制。这些数据与小鼠肝脏中存在HMG CoA还原酶的多价反馈调节机制相一致，在该机制中，酶的抑制需要一种固醇和一种源自甲羟戊酸的非固醇物质。通过阻断甲羟戊酸的合成，莫纳可林激活了这种调节机制，进而导致肝脏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，可能在增强莫纳可林作为降胆固醇药物的有效性方面被证明是有用的。
