Chao Y S, Kroon P A, Yamin T T, Thompson G M, Alberts A W
Biochim Biophys Acta. 1983 Nov 29;754(2):134-41. doi: 10.1016/0005-2760(83)90154-6.
Rabbits fed a wheat starch-casein diet develop a marked hypercholesterolemia and have a slower rate of removal of rabbit 125I-labeled low density lipoproteins (LDL) from plasma. Treating rabbits with mevinolin, a highly potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, at a daily dose of 20 mg per animal prevents the increase in plasma and LDL cholesterol. The mevinolin effect is mediated through an increased rate of removal of rabbit 125I-labeled LDL from plasma. To study the role of mevinolin on the regulation of the hepatic LDL receptor in rabbits, the binding of 125I-labeled LDL and 125I-labeled beta-VLDL (beta-migrating very-low-density lipoproteins) to liver membranes prepared from rabbits fed the wheat starch-casein diet with or without mevinolin was investigated. Liver membranes from wheat starch-casein-fed rabbits have no demonstrable EDTA-sensitive binding activity of 125I-labeled LDL and low (37 ng/mg protein) binding activity of 125I-labeled beta-VLDL. Treatment of the wheat starch-casein fed rabbits with mevinolin results in high levels of specific EDTA-sensitive binding of 125I-labeled LDL (28.7 ng/mg protein) and 125I-labeled beta-VLDL (120 ng/mg protein). To assess the functional role of the hepatic LDL receptor in response to mevinolin, the catabolism of 125I-labeled LDL by perfused rabbit livers was studied. Perfused livers from mevinolin-treated rabbits show a 3.3-fold increase in the rate of receptor-dependent catabolism of 125I-labeled LDL (4.6% X h-1) when compared with that of livers from rabbits not treated with mevinolin (1.4% X h-1). Thus, these studies demonstrate that mevinolin prevents the increase of plasma LDL cholesterol level in rabbits fed a wheat starch-casein diet by regulating the levels of hepatic LDL-binding sites and the rate of receptor-dependent catabolism of LDL by the liver.
喂食小麦淀粉 - 酪蛋白饮食的兔子会出现明显的高胆固醇血症，并且从血浆中清除兔125I标记的低密度脂蛋白（LDL）的速率较慢。以每只动物每日20毫克的剂量用美伐他汀（一种3 - 羟基 - 3 - 甲基戊二酰辅酶A还原酶的高效竞争性抑制剂）治疗兔子，可防止血浆和LDL胆固醇升高。美伐他汀的作用是通过提高从血浆中清除兔125I标记的LDL的速率来介导的。为了研究美伐他汀对兔子肝脏LDL受体调节的作用，研究了125I标记的LDL和125I标记的β - VLDL（β迁移极低密度脂蛋白）与喂食小麦淀粉 - 酪蛋白饮食且添加或不添加美伐他汀的兔子制备的肝细胞膜的结合情况。喂食小麦淀粉 - 酪蛋白的兔子的肝细胞膜对125I标记的LDL没有可证明的EDTA敏感结合活性，对125I标记的β - VLDL的结合活性较低（37纳克/毫克蛋白质）。用美伐他汀治疗喂食小麦淀粉 - 酪蛋白的兔子会导致125I标记的LDL（28.7纳克/毫克蛋白质）和125I标记的β - VLDL（120纳克/毫克蛋白质）出现高水平的特异性EDTA敏感结合。为了评估肝脏LDL受体对美伐他汀反应的功能作用，研究了灌注兔肝脏对125I标记的LDL的分解代谢。与未用美伐他汀治疗的兔子的肝脏相比，用美伐他汀治疗的兔子的灌注肝脏显示125I标记的LDL的受体依赖性分解代谢速率增加了3.3倍（4.6%×小时-1对1.4%×小时-1）。因此，这些研究表明，美伐他汀通过调节肝脏LDL结合位点的水平以及肝脏对LDL的受体依赖性分解代谢速率，防止喂食小麦淀粉 - 酪蛋白饮食的兔子血浆LDL胆固醇水平升高。
