Mechanism of action of gemfibrozil on lipoprotein metabolism.
Mechanism of action of gemfibrozil on lipoprotein metabolism.
复制标题
DOI：
10.1172/jci111879
复制
发表时间：
1985-05
期刊：
影响因子：
--
通讯作者：
K. Saku;P. Gartside;B. Hynd;M. Kashyap
中科院分区：
文献类型：
--
作者：
K. Saku;P. Gartside;B. Hynd;M. Kashyap
吉非罗齐是一种有效的调脂药物，其主要作用是在多种原发和继发性血脂异常症中升高血浆高密度脂蛋白(HDL)和降低甘油三酯(TG)。其作用机制尚不清楚。对6例家族性内源性高甘油三酯血症合并空腹乳糜体微粒血症(V型脂蛋白表型)合并低密度脂蛋白血症(高密度脂蛋白缺乏症)患者进行饮食治疗，病情稳定后给予吉非罗齐1200 mg/d治疗。每例患者均住进具有代谢厨房设施的临床研究中心，在吉非罗齐治疗8wk前和治疗后即刻进行高密度脂蛋白和甘油三酯代谢的调查。吉非罗齐使血浆高密度脂蛋白胆固醇、载脂蛋白AI和载脂蛋白II较基线分别升高36%、29%和38%。血浆甘油三酯下降54%。通过分析注射125I标记的自体高密度脂蛋白后的特定放射性衰减曲线，评价载脂蛋白AI和载脂蛋白AII的代谢动力学。吉非罗齐使载脂蛋白AI和载脂蛋白AII的合成率分别增加27%和34%，而不改变部分分解代谢率。梯度凝胶电泳法和高密度脂蛋白组成分析显示，吉非罗齐刺激载脂蛋白AI和载脂蛋白AII的合成与血浆中较小(和较重)的高密度脂蛋白颗粒的出现有关。吉非罗齐治疗后肝素后肝外脂蛋白脂酶活性显著升高25%，与血浆中出现较小的极低密度脂蛋白颗粒有关，其载脂蛋白CIII/CII比值降低。这些数据表明吉非罗齐通过刺激血浆高密度脂蛋白的合成来提高其水平。吉非罗齐诱导的高密度脂蛋白转运(周转)增加可能是这些患者增加组织胆固醇清除的重要原因。
Gemfibrozil is a potent lipid regulating drug whose major effects are to increase plasma high density lipoproteins (HDL) and to decrease plasma triglycerides (TG) in a wide variety of primary and secondary dyslipoproteinemias. Its mechanism of action is not clear. Six patients with primary familial endogenous hypertriglyceridemia with fasting chylomicronemia (type V lipoprotein phenotype) with concurrent subnormal HDL cholesterol levels (HDL deficiency) were treated initially by diet and once stabilized, were given gemfibrozil (1,200 mg/d). Each patient was admitted to the Clinical Research Center with metabolic kitchen facilities, for investigation of HDL and TG metabolism immediately before and after 8 wk of gemfibrozil treatment. Gemfibrozil significantly increased plasma HDL cholesterol, apolipoprotein (apo) AI, and apo AII by 36%, 29%, and 38% from base line, respectively. Plasma TG decreased by 54%. Kinetics of apo AI and apo AII metabolism were assessed by analysis of the specific radioactivity decay curves after injection of autologous HDL labeled with 125I. Gemfibrozil increased synthetic rates of apo AI and apo AII by 27% and 34%, respectively, without changing the fractional catabolic rates. Stimulation of apo AI and apo AII synthesis by gemfibrozil was associated with the appearance in plasma of smaller (and heavier) HDL particles as assessed by gradient gel electrophoresis and HDL composition. Postheparin extra-hepatic lipoprotein lipase activity increased significantly by 25% after gemfibrozil, and was associated with the appearance in plasma of smaller very low density lipoprotein particles whose apo CIII:CII ratio was decreased. These data suggest that gemfibrozil increases plasma HDL levels by stimulating their synthesis. Increased transport (turnover) of HDL induced by gemfibrozil may be significant in increasing tissue cholesterol removal in these patients.