Reihnér E, Rudling M, Ståhlberg D, Berglund L, Ewerth S, Björkhem I, Einarsson K, Angelin B
Department of Surgery, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
N Engl J Med. 1990 Jul 26;323(4):224-8. doi: 10.1056/NEJM199007263230403.
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 cholesterol synthesis by one of these agents (pravastatin) on the hepatic metabolism of cholesterol in patients with gallstone disease who were scheduled to undergo cholecystectomy.
Ten patients were treated with pravastatin (20 mg twice a day) for three weeks before cholecystectomy; 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.
Pravastatin therapy reduced plasma total cholesterol by 26 percent and LDL cholesterol by 39 percent (P less than 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 less than 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 11.8-fold (1344 +/- 311 vs. 105 +/- 14 pmol per minute per milligram of protein in the controls; P less than 0.001). The expression of LDL receptors was increased by 180 percent (P less than 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.
Inhibition of hepatic HMG-CoA reductase by pravastatin results in an increased expression of hepatic LDL receptors, which explains the lowered plasma levels of LDL cholesterol.
胆固醇生物合成限速酶3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂现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行胆囊切除术的胆结石病患者肝脏胆固醇代谢的影响。
10例患者在胆囊切除术前接受普伐他汀治疗（每日2次，每次20mg），为期3周；20例未接受治疗的患者作为对照。术中从每位患者获取肝脏标本，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。
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）。游离羊毛甾醇（胆固醇的一种前体，其浓度反映体内胆固醇合成速率）的血清水平降低63%（P<0.005），表明胆固醇的从头生物合成减少。在无抑制剂的情况下体外分析时，微粒体HMG-CoA还原酶活性增加了11.8倍（对照组为每分钟每毫克蛋白质105±14pmol，治疗组为1344±311pmol；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）的活性不受治疗影响。
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胆固醇水平降低的原因。
