Menéndez R, Más R, Pérez J, González R M, Jiménez S
Center of Natural Products, National Center for Scientific Research, PO Box 6880, Havana, Cuba.
Can J Physiol Pharmacol. 2004 Jan;82(1):22-9. doi: 10.1139/y03-123.
D-003 is a mixture of very long chain saturated fatty acids (VLCSFA) purified from sugar cane wax with cholesterol-lowering effects proven in animal models and healthy volunteers. D-003 inhibits cholesterol biosynthesis through the regulation of HMG-CoA reductase activity. Rabbits fed diets enriched with casein develop endogenous hypercholesterolemia (EH), making them a very useful model for determining the mechanism of action of drugs affecting lipids. We examined whether D-003 prevented EH. Rabbits were fed a casein diet for 4 weeks, administered simultaneously with D-003 (5, 50, and 100 mg.kg-1.day-1). As expected, nontreated rabbits became hypercholesterolemic; however, as early as 15 days following administration, the treated group (50 and 100 mg.kg-1.day-1) had significantly decreased total cholesterol and low-density lipoprotein cholesterol (LDL-C). Triglycerides were not affected; however, at study completion, HDL-C levels significantly increased at all the doses assayed. D-003 inhibited de novo synthesis of cholesterol, since the incorporation of 3H2O into sterols in the liver and proximal small bowel was significantly depressed. Also, D-003 significantly raised the rate of removal of [125I]-LDL from serum and significantly elevated [125I]-LDL binding activity to liver homogenates. Taken together, these results show that the efficacy of D-003 in reducing casein-derived hypercholesterolemia could involve, at least partially, an inhibition of hepatic cholesterol biosynthesis, which may elicit a decreased cholesterol concentration in hepatocytes, preventing the loss of hepatic LDL receptors induced by casein administration. However, since casein-induced hypercholesterolemia is also a consequence of a stimulation of cholesterol absorption in the lumen and an increase of the output of cholesterol associated with LDL, the effect of D-003 on cholesterol absorption and LDL synthesis by the liver should be investigated.
D - 003是一种从甘蔗蜡中提纯的极长链饱和脂肪酸（VLCSFA）混合物，其降胆固醇作用在动物模型和健康志愿者身上已得到证实。D - 003通过调节HMG - CoA还原酶活性来抑制胆固醇生物合成。用富含酪蛋白的饲料喂养兔子会引发内源性高胆固醇血症（EH），这使其成为确定影响脂质药物作用机制的非常有用的模型。我们研究了D - 003是否能预防EH。给兔子喂食酪蛋白饲料4周，同时给予D - 003（5、50和100毫克·千克⁻¹·天⁻¹）。不出所料，未治疗的兔子出现了高胆固醇血症；然而，早在给药后15天，治疗组（50和100毫克·千克⁻¹·天⁻¹）的总胆固醇和低密度脂蛋白胆固醇（LDL - C）就显著降低。甘油三酯未受影响；然而，在研究结束时，所有测定剂量的高密度脂蛋白胆固醇（HDL - C）水平均显著升高。D - 003抑制了胆固醇的从头合成，因为肝脏和近端小肠中³H₂O掺入固醇的量显著降低。此外，D - 003显著提高了血清中[¹²⁵I] - LDL的清除率，并显著提高了[¹²⁵I] - LDL与肝脏匀浆的结合活性。综上所述，这些结果表明，D - 003降低酪蛋白源性高胆固醇血症的功效可能至少部分涉及对肝脏胆固醇生物合成的抑制，这可能导致肝细胞中胆固醇浓度降低，防止因给予酪蛋白而诱导的肝脏LDL受体丢失。然而，由于酪蛋白诱导的高胆固醇血症也是肠腔中胆固醇吸收增加以及与LDL相关的胆固醇输出增加的结果，因此应研究D - 003对肝脏胆固醇吸收和LDL合成的影响。
