Bocos C, Castro M, Quack G, Herrera E
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain.
Biochim Biophys Acta. 1993 Jul 1;1168(3):340-7. doi: 10.1016/0005-2760(93)90191-b.
To contribute to the understanding of the hypolipidemic action of etofibrate, which is the 1,2-ethandiol ester of clofibric acid and nicotinic acid, 300 mg of this drug/kg body weight or of the medium were administered daily by a stomach tube to normolipidemic rats. Some animals were decapitated at the 10th day of daily treatment (prolonged treatment), whereas others were studied at different times after one single administration (acute treatment). In animals on prolonged treatment etofibrate decreased plasma levels of cholesterol, triacylglycerols, free fatty acids (FFA) and glycerol, as well as the total and unesterified cholesterol concentrations, in liver microsomes. In these rats, etofibrate increased the activity of liver cytosolic glycerol-3-P dehydrogenase, whereas it decreased the activity of both microsomal HMG-CoA reductase and cholesterol 7 alpha-hydroxylase and did not affect acyl-CoA: cholesterol acyltransferase (ACAT). At 3, 5 and 7 h after acute treatment, etofibrate decreased plasma levels of triacylglycerols, glycerol and FFA, and this effect disappeared at 24 h, whereas plasma cholesterol did not change 3 h after etofibrate but decreased at 5 and 7 h and remained low after 24 h, and a similar change was found in the liver microsomes free cholesterol concentration. However, with the exception of a significant reduction in cytosolic glycerol-3-P dehydrogenase at 7 h and in ACAT at 5 h, acute etofibrate treatment did not affect the activity of the liver enzymes studied. At low concentrations (10(-5) M) in the incubation medium, etofibrate decreased the release of both FFA and glycerol by epididymal fat pad pieces incubated in vitro. These findings together with those previously reported by us in rats using a similar etofibrate treatment protocol [6] indicate that etofibrate decreases the availability of lipolytic products in the liver by acting on their release from adipose tissue and on their intrinsic hepatic metabolism. Consequently, this drug would decrease liver VLDL triacylglycerol synthesis and secretion, which together with facilitating the clearance of circulating triacylglycerols causes its hypotriglyceridemic effect. The hypocholesterolemic effect of etofibrate after acute treatment may be a secondary consequence of the reduced liver VLDL production caused by decreased adipose tissue lipolysis, but after prolonged treatment, this effect also seems to be influenced by the inhibition of HMG-CoA reductase activity which would reduce cholesterol synthesis.
为了有助于理解益多酯（氯贝酸与烟酸的1,2 - 乙二醇酯）的降血脂作用，每天通过胃管给正常血脂大鼠灌胃300毫克该药物/千克体重或灌胃等量的溶剂。在每日治疗的第10天（长期治疗），处死部分动物，而其他动物在单次给药后的不同时间进行研究（急性治疗）。在长期治疗的动物中，益多酯降低了血浆中胆固醇、三酰甘油、游离脂肪酸（FFA）和甘油的水平，以及肝微粒体中总胆固醇和未酯化胆固醇的浓度。在这些大鼠中，益多酯增加了肝细胞溶质甘油 - 3 - 磷酸脱氢酶的活性，而降低了微粒体HMG - CoA还原酶和胆固醇7α - 羟化酶的活性，并且不影响酰基辅酶A：胆固醇酰基转移酶（ACAT）。急性治疗后3、5和7小时，益多酯降低了血浆中三酰甘油、甘油和FFA的水平，并且这种作用在24小时消失，而益多酯给药后3小时血浆胆固醇没有变化，但在5和7小时降低并且在24小时后保持低水平，并且在肝微粒体游离胆固醇浓度中发现了类似的变化。然而，除了在7小时时细胞溶质甘油 - 3 - 磷酸脱氢酶和在5小时时ACAT有显著降低外，急性益多酯治疗不影响所研究的肝脏酶的活性。在孵育培养基中低浓度（10^(-5) M）时，益多酯降低了体外孵育的附睾脂肪垫片释放FFA和甘油的量。这些发现与我们之前在大鼠中使用类似的益多酯治疗方案所报道的结果[6]一起表明，益多酯通过作用于脂肪组织中脂解产物的释放及其内在的肝脏代谢来降低肝脏中脂解产物的可用性。因此，这种药物将减少肝脏极低密度脂蛋白（VLDL）三酰甘油的合成和分泌，这与促进循环三酰甘油的清除一起导致其降甘油三酯作用。益多酯急性治疗后的降胆固醇作用可能是脂肪组织脂解减少导致肝脏VLDL产生减少的继发结果，但在长期治疗后，这种作用似乎也受到HMG - CoA还原酶活性抑制的影响，这将减少胆固醇的合成。
