Burnett J R, Wilcox L J, Telford D E, Kleinstiver S J, Barrett P H, Newton R S, Huff M W
Department of Medicine, University of Western Ontario, London, Canada.
Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2589-600. doi: 10.1161/01.atv.17.11.2589.
In the present studies, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor atorvastatin was used to test the hypothesis that inhibition of cholesterol biosynthesis in vivo with a consequent reduction in the availability of hepatic cholesterol for lipoprotein synthesis, would (1) reduce very low density lipoprotein (VLDL) apolipoprotein B (apoB) secretion into the plasma, (2) reduce the conversion of VLDL apoB to LDL apoB, and (3) reduce LDL apoB direct synthesis. ApoB kinetic studies were carried out in six control miniature pigs and in six animals after 21 days of administration of atorvastatin (3 mg/kg per day). Pigs were fed a fat- (34% of calories; polyunsaturated to monounsaturated to saturated ratio, 1:1:1) and cholesterol- (400 mg/d cholesterol; 0.1%; 0.2 mg/kcal) containing pig chow-based diet. Atorvastatin treatment significantly reduced plasma total cholesterol, LDL cholesterol, total triglyceride, and VLDL triglyceride concentrations by 16%, 31%, 19%, and 28%, respectively (P < .01). Autologous 131I-VLDL, 125I-LDL, and [3H]leucine were injected simultaneously into each pig, and apoB kinetic data were analyzed using multicompartmental analysis (SAAM II). The VLDL apoB pool size decreased by 29% (0.46 versus 0.65 mg/kg; P = .002), which was entirely due to a 34% reduction in the VLDL apoB production rate (PR) (1.43 versus 2.19 mg/kg per hour; P = .027). The fractional catabolic rate (FCR) was unchanged. The LDL apoB pool size decreased by 30% (4.74 versus 6.75 mg/kg; P = .0004), which was due to a 22% reduction in the LDL apoB PR (0.236 versus 0.301 mg/kg per hour; P = .004), since the FCR was unchanged. The reduction in LDL apoB PR was primarily due to a 34% decrease in conversion of VLDL apoB to LDL apoB; however, this reduction was not statistically significant (P = .114). Hepatic apoB mRNA abundance quantitated by RNase protection assay was decreased by 13% in the atorvastatin-treated animals (P = .003). Hepatic and intestinal LDL receptor mRNA abundances were not affected. We conclude that inhibition of hepatic HMG-CoA reductase by atorvastatin reduces both VLDL and LDL apoB concentrations, primarily by decreasing apoB secretion into the plasma and not by an increase in hepatic LDL receptor expression. This decrease in apoB secretion may, in part, be due to a reduction in apoB mRNA abundance.
在本研究中，使用3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂阿托伐他汀来验证以下假设：体内抑制胆固醇生物合成，从而减少肝脏用于脂蛋白合成的胆固醇供应，将（1）减少极低密度脂蛋白（VLDL）载脂蛋白B（apoB）分泌到血浆中，（2）减少VLDL apoB向低密度脂蛋白（LDL）apoB的转化，以及（3）减少LDL apoB的直接合成。对6只对照小型猪和6只给予阿托伐他汀（每天3mg/kg）21天后的动物进行了apoB动力学研究。给猪喂食基于猪饲料的饮食，其中脂肪含量为34%（热量），多不饱和脂肪酸与单不饱和脂肪酸与饱和脂肪酸的比例为1:1:1，胆固醇含量为400mg/d（胆固醇）（0.1%；0.2mg/kcal）。阿托伐他汀治疗显著降低了血浆总胆固醇、LDL胆固醇、总甘油三酯和VLDL甘油三酯浓度，分别降低了16%、31%、19%和28%（P<.01）。将自体131I-VLDL、125I-LDL和[3H]亮氨酸同时注射到每只猪体内，并使用多室分析（SAAM II）分析apoB动力学数据。VLDL apoB池大小减少了29%（0.46对0.65mg/kg；P=.002），这完全是由于VLDL apoB产生率（PR）降低了34%（1.43对2.19mg/kg每小时；P=.027）。分解代谢率（FCR）未改变。LDL apoB池大小减少了30%（4.74对6.75mg/kg；P=.0004），这是由于LDL apoB PR降低了22%（0.236对0.301mg/kg每小时；P=.004），因为FCR未改变。LDL apoB PR的降低主要是由于VLDL apoB向LDL apoB的转化减少了34%；然而，这种减少在统计学上不显著（P=.114）。通过核糖核酸酶保护试验定量的肝脏apoB mRNA丰度在阿托伐他汀治疗的动物中降低了13%（P=.003）。肝脏和肠道LDL受体mRNA丰度未受影响。我们得出结论，阿托伐他汀抑制肝脏HMG-CoA还原酶可降低VLDL和LDL apoB浓度，主要是通过减少apoB分泌到血浆中，而不是通过增加肝脏LDL受体表达。apoB分泌的这种减少可能部分归因于apoB mRNA丰度的降低。
