INFLUENCE OF PRAVASTATIN, A SPECIFIC INHIBITOR OF HMG-COA REDUCTASE, ON HEPATIC-METABOLISM OF CHOLESTEROL
INFLUENCE OF PRAVASTATIN, A SPECIFIC INHIBITOR OF HMG-COA REDUCTASE, ON HEPATIC-METABOLISM OF CHOLESTEROL
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DOI：
10.1056/nejm199007263230403
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发表时间：
1990-07-26
影响因子：
158.5
通讯作者：
ANGELIN, B
中科院分区：
文献类型：
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作者：
REIHNER, E;RUDLING, M;ANGELIN, B
背景：胆固醇生物合成限速酶 3-羟基-3-甲基-戊二酰辅酶 A (HMG-CoA) 还原酶的抑制剂现在经常用于治疗高胆固醇血症。我们研究了其中一种药物（普伐他汀）特异性抑制胆固醇合成对计划接受胆囊切除术的胆石病患者胆固醇肝脏代谢的影响。方法：10 名患者在胆囊切除术前接受普伐他汀（20 mg，每天两次）治疗三周； 20名未接受治疗的患者作为对照。手术时从每位患者身上获取肝脏标本，测定胆固醇代谢中限速酶的活性以及低密度脂蛋白（LDL）受体结合活性。结果：普伐他汀治疗使血浆总胆固醇降低 26%，LDL 胆固醇降低 39%（P < 0.005）。游离拉索甾醇（胆固醇的前体，其浓度反映体内胆固醇合成速率）的血清水平降低了 63% (P < 0.005)，表明胆固醇从头生物合成减少。在没有抑制剂的情况下进行体外分析时，微粒体 HMG-CoA 还原酶活性增加了 118 倍（对照中每分钟每毫克蛋白质 1344.+-.311 对比 105.+-.14 pmol；P < 0.001）。 LDL受体的表达增加了180%（P<0.005），而胆固醇7α-羟化酶（控制胆汁酸合成）和酰基辅酶A：胆固醇O-酰基转移酶（调节胆固醇酯化）的活性未受到治疗的影响。结论：普伐他汀抑制肝脏 HMG-CoA 还原酶导致肝脏 LDL 受体表达增加，这解释了血浆 LDL 胆固醇水平降低。
Background: Inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, are now used frequently to treat hypercholesterolemia. We studied the effects of specific inhibition of choelsterol synthesis by one of these agents (pravastatin) on the hepatic metabolism of cholesterol in patients with gallstone disease who were scheduled to undergo cholecystectomy. Methods: Ten patients were treated with pravastatin (20 mg twice a day) for three weeks before cholescystectomy; 20 patients not treated served as controls. A liver specimen was obtained from each patient at operation, and the activities of rate-determining enzymes in cholesterol metabolism as well as low-density-lipoprotein (LDL)-receptor binding activity were determined. Results: Pravastatin therapy reduced plasma total cholesterol by 26 percent and LDL cholesterol by 39 percent (P < 0.005). Serum levels of free lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, decreased by 63 percent (P < 0.005), indicating reduced de novo biosynthesis of cholesterol. Microsomal HMG-CoA reductase activity, when analyzed in vitro in the absence of the inhibitor, was increased 118.-fold (1344 .+-. 311 vs. 105 .+-. 14 pmol per minute per milligram of protein in the controls; P < 0.001). The expression of LDL receptors was increased by 180 percent (P < 0.005), whereas the activities of cholesterol 7.alpha.-hydroxylase (which governs bile acid synthesis) and of acyl-coenzyme A:cholesterol O-acyltransferase (which regulates cholesterol esterification) were unaffected by treatment. Conclusions: Inhibiton of hepatic HMG-CoA redcutase by pravastatin results in an increased expression of hepatic LDL receptors, which explains the lowered plasma levels of LDL cholesterol.