Krause B R, Newton R S
J Lipid Res. 1985 Aug;26(8):940-9.
Gemfibrozil (Lopid) is a new plasma lipid-regulating drug that decreases very low and low density lipoprotein (VLD/LDL) and increases high density lipoprotein (HDL) concentrations in man. The present experiments tested the effects of gemfibrozil on plasma lipoproteins and apolipoproteins in rats fed high fat/high cholesterol diets. Compared to chow-fed rats, cholesterol feeding for 2 weeks (20% olive oil/2% cholesterol) produced the expected increases in VLDL and intermediate density lipoprotein (IDL) while lowering plasma HDL. This was documented by using three methods of lipoprotein isolation: sequential ultracentrifugation, density gradient ultracentrifugation, and agarose gel filtration. Gemfibrozil gavaged at 50 mg/kg per day for 2 weeks during cholesterol feeding prevented these changes such that lipoprotein patterns were similar to those in chow-fed animals. Whole plasma apoE and apoA-I concentrations were decreased and apoB increased due to cholesterol feeding as determined by electroimmunoassay, but again gemfibrozil treatment prevented these diet-induced alterations. Gradient polyacrylamide gel electrophoresis patterns of the total d less than 1.21 g/ml lipoprotein fractions reflected the changes in apolipoprotein concentrations and further demonstrated a greater increase of apoBl compared to apoBh in cholesterol-fed rats. Gemfibrozil lowered the concentration of both apoB variants and prevented the shift of apoE from HDL to lower density lipoproteins. Changes in the distribution of apoE were confirmed using agarose gel column chromatography followed by electroimmunoassay. These methods also revealed a shift of apoA-IV from HDL to the d greater than 1.21 g/ml, lipoprotein-free fraction with gemfibrozil treatment when blood was taken from fasted or postabsorptive animals. Since it was also noted that in chow-fed rats more apoA-IV was present in the d greater than 1.21 g/ml fraction in the postabsorptive or fed state compared to fasted animals, it could be postulated that the shift of apoA-IV into this fraction in gemfibrozil-treated rats is related to an accelerated clearance of chylomicrons. It is concluded that gemfibrozil largely prevents the accumulation of abnormal lipoproteins in this model of dyslipoproteinemia, and that apoE may play a critical role in this normalization process.
吉非贝齐（诺衡）是一种新型血浆脂质调节药物，可降低人体极低密度脂蛋白和低密度脂蛋白（VLD/LDL）水平，并提高高密度脂蛋白（HDL）浓度。本实验测试了吉非贝齐对高脂/高胆固醇饮食喂养大鼠血浆脂蛋白和载脂蛋白的影响。与正常饮食喂养的大鼠相比，喂食胆固醇2周（20%橄榄油/2%胆固醇）会使极低密度脂蛋白和中间密度脂蛋白（IDL）预期增加，同时降低血浆高密度脂蛋白。这通过三种脂蛋白分离方法得以证实：连续超速离心、密度梯度超速离心和琼脂糖凝胶过滤。在喂食胆固醇期间，每天以50mg/kg的剂量灌胃给予吉非贝齐2周，可防止这些变化，使脂蛋白模式与正常饮食喂养的动物相似。通过免疫电泳测定发现，由于喂食胆固醇，全血浆载脂蛋白E和载脂蛋白A-I浓度降低，载脂蛋白B增加，但吉非贝齐治疗再次防止了这些饮食诱导的改变。总密度小于1.21g/ml脂蛋白组分的梯度聚丙烯酰胺凝胶电泳图谱反映了载脂蛋白浓度的变化，并进一步表明，与正常饮食喂养的大鼠相比，喂食胆固醇的大鼠中载脂蛋白B1的增加幅度大于载脂蛋白Bh。吉非贝齐降低了两种载脂蛋白B变体的浓度，并防止了载脂蛋白E从高密度脂蛋白向低密度脂蛋白的转移。使用琼脂糖凝胶柱色谱法随后进行免疫电泳，证实了载脂蛋白E分布的变化。这些方法还显示，当从禁食或吸收后动物采血时，经吉非贝齐治疗后，载脂蛋白A-IV从高密度脂蛋白转移到密度大于1.21g/ml的无脂蛋白组分中。由于还注意到，与禁食动物相比，正常饮食喂养的大鼠在吸收后或进食状态下，密度大于1.21g/ml的组分中存在更多的载脂蛋白A-IV，因此可以推测，在吉非贝齐治疗的大鼠中，载脂蛋白A-IV向该组分的转移与乳糜微粒清除加速有关。结论是，在这种血脂蛋白异常模型中，吉非贝齐在很大程度上防止了异常脂蛋白的积累，并且载脂蛋白E可能在这一正常化过程中起关键作用。
