Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase by oxysterol by-products of cholesterol biosynthesis. Possible mediators of low density lipoprotein action.
Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase by oxysterol by-products of cholesterol biosynthesis. Possible mediators of low density lipoprotein action.
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DOI：
10.1016/s0021-9258(17)42859-6
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发表时间：
1984-06
期刊：
影响因子：
--
通讯作者：
S. Panini;R. Sexton;H. Rudney
中科院分区：
文献类型：
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作者：
S. Panini;R. Sexton;H. Rudney
利用3- β -[2-（二乙基氨基）乙氧基]androst-5-en-17-one （U18666A）对培养大鼠肠上皮细胞中3-羟基-3-甲基戊二酰辅酶A还原酶（EC 1.1.1.34，还原酶）活性的调节进行了研究，该酶是2,3-氧化角鲨烯环化酶（EC 5.4.99.7，环化酶）的抑制剂，可引起细胞积聚角鲨烯2,3:22,23-二氧化（Sexton， R. C., Panini， S.R., Azran， F., and Rudney， H. (1983) Biochemistry 22, 5687-5692）。用U18666A （5-50 ng/ml）处理细胞可导致还原酶活性的进行性抑制。药物水平的进一步增加反而降低了抑制作用，因此在1微克/毫升的水平下，没有观察到酶活性的抑制作用。角鲨烯2,3:22,23- 2的细胞代谢为具有极性甾醇色谱性质的化合物，导致还原酶活性的抑制，而U18666A（1微克/毫升）可以阻止这种抑制。该药物不能阻止25-羟基胆固醇或甲维洛内酯对酶活性的抑制作用，但完全消除了低密度脂蛋白的抑制作用。U18666A预处理不影响细胞降解低密度脂蛋白载脂蛋白或胆固醇酯成分的能力。这些结果表明，角鲨烯2,3:22,23- 2衍生的氧化甾醇可能作为还原酶的生理调节剂，并提出了低密度脂蛋白对还原酶的抑制作用可能部分或全部由这些内源性氧化甾醇通过不完全抑制环化酶而产生。
Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34, reductase) activity was studied in cultured rat intestinal epithelial cells using 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one ( U18666A ), an inhibitor of 2,3- oxidosqualene cyclase (EC 5.4.99.7, cyclase) that causes cellular accumulation of squalene 2,3:22,23-dioxide ( Sexton , R. C., Panini , S.R., Azran , F., and Rudney , H. (1983) Biochemistry 22, 5687-5692). Treatment of cells with U18666A (5-50 ng/ml) caused a progressive inhibition of reductase activity. Further increases in the level of the drug paradoxically lessened the inhibition such that at a level of 1 microgram/ml, no inhibition of enzyme activity was observed. Cellular metabolism of squalene 2,3:22,23-dioxide to compounds with the chromatographic properties of polar sterols led to an inhibition of reductase activity that could be prevented by U18666A (1 microgram/ml). The drug was unable to prevent the inhibition of enzyme activity by 25-hydroxycholesterol or mevalonolactone, but totally abolished the inhibitory action of low density lipoproteins. Pretreatment with U18666A did not affect the ability of cells to degrade either the apoprotein or the cholesteryl ester component of low density lipoproteins. These results suggest that oxysterols derived from squalene 2,3:22,23-dioxide may act as physiological regulators of reductase and raise the possibility that the suppressive action of low density lipoproteins on reductase may be partially or wholly mediated by such endogenous oxysterols generated through incomplete inhibition of the cyclase.