Khan B V, Fungwe T V, Wilcox H G, Heimberg M
Department of Pharmacology, University of Tennessee-Memphis 38163.
Biochim Biophys Acta. 1990 Jun 14;1044(3):297-304. doi: 10.1016/0005-2760(90)90073-7.
Rats were fed for 1 week with a standard chow diet, a diet supplemented with lovastatin (0.1%), or a diet supplemented with both lovastatin and cholesterol (0.1/0.1%), to study effects of depletion of a putative hepatic metabolic pool of cholesterol on secretion of the very-low-density lipoprotein (VLDL) in the intact animal. Triton WR-1339 (50 mg/100 g body wt.) or the 0.9% NaCl vehicle alone was given intravenously via a sacral vein. Treatment with lovastatin decreased the secretion of all plasma VLDL lipids, the average decrease after 2 h for VLDL triacylglycerol, phospholipid, cholesterol and cholesteryl ester being 45%. When both lovastatin and cholesterol were included in the diet, the secretion of VLDL triacylglycerol and phospholipid was similar to that of control animals, while secretion of VLDL cholesterol and cholesteryl ester was increased. Treatment with lovastatin reduced the hepatic concentration of cholesteryl esters 42% without affecting free cholesterol. In separate experiments, in vivo synthesis of cholesterol was determined 1 h after intraperitoneal administration of 3H2O. Incorporation into hepatic and plasma free cholesterol and cholesteryl esters was greater in the rats fed lovastatin than in control animals, concurrent with decreased VLDL secretion. The metabolism of VLDL was determined in vivo by intravenous administration of 125I-VLDL. The fractional clearance rates of 125I-VLDL from the plasma were similar among the three experimental groups. Synthesis of hepatic triacylglycerol from [1-14C]oleate in vivo was similar in all treatment groups; incorporation into plasma triacylglycerol was reduced with lovastatin treatment and reversed partially by inclusion of 0.1% cholesterol in the lovastatin diet. Plasma concentrations of triacylglycerol followed patterns of incorporation of [1-14C]oleate. Triacylglycerol concentration in the liver increased when cholesterol was included in the diet. In companion experiments, incorporation of [1-14C]oleate into perfusate triacylglycerol in vitro was reduced with perfused livers from lovastatin-treated animals. In these experiments, oxidation of fatty acid into CO2 and perchloric acid-soluble counts was not affected by lovastatin, added either to the diet or to the perfusate in vitro. It appears, therefore, that lovastatin does not affect triacylglycerol synthesis or fatty acid oxidation, which per se might reduce formation and secretion of VLDL. These data, therefore, strengthen the hypothesis that reduced availability of cholesterol in a putative hepatic metabolic pool, required for secretion and transport of triacylglycerol in the VLDL, is a factor contributing to decreased secretion of the VLDL.
为研究假定的肝脏胆固醇代谢池耗竭对完整动物极低密度脂蛋白（VLDL）分泌的影响，将大鼠分别用标准饲料、添加洛伐他汀（0.1%）的饲料或同时添加洛伐他汀和胆固醇（0.1%/0.1%）的饲料喂养1周。通过骶静脉静脉注射给予Triton WR - 1339（50 mg/100 g体重）或单独的0.9% NaCl载体。洛伐他汀治疗可降低所有血浆VLDL脂质的分泌，2小时后VLDL三酰甘油、磷脂、胆固醇和胆固醇酯的平均降低率为45%。当饲料中同时包含洛伐他汀和胆固醇时，VLDL三酰甘油和磷脂的分泌与对照动物相似，而VLDL胆固醇和胆固醇酯的分泌增加。洛伐他汀治疗可使肝脏胆固醇酯浓度降低42%，而不影响游离胆固醇。在单独的实验中，腹腔注射3H2O 1小时后测定体内胆固醇的合成。与对照动物相比，喂食洛伐他汀的大鼠肝脏和血浆游离胆固醇及胆固醇酯中的掺入量更高，同时VLDL分泌减少。通过静脉注射125I - VLDL在体内测定VLDL的代谢。三个实验组中125I - VLDL从血浆中的分数清除率相似。所有治疗组中，体内[1 - 14C]油酸合成肝脏三酰甘油的情况相似；洛伐他汀治疗可降低[1 - 14C]油酸掺入血浆三酰甘油的量，而在洛伐他汀饲料中添加0.1%胆固醇可部分逆转这种情况。血浆三酰甘油浓度遵循[1 - 14C]油酸掺入模式。当饲料中包含胆固醇时，肝脏中三酰甘油浓度升高。在相关实验中，用洛伐他汀处理动物的灌注肝脏进行体外实验时，[1 - 14C]油酸掺入灌注液三酰甘油的量减少。在这些实验中，无论是添加到饲料中还是体外灌注液中，洛伐他汀均不影响脂肪酸氧化为CO2和高氯酸可溶性物质的过程。因此，似乎洛伐他汀不影响三酰甘油合成或脂肪酸氧化，而这本身可能会减少VLDL的形成和分泌。因此，这些数据强化了这样一种假说，即VLDL中三酰甘油分泌和运输所需的假定肝脏代谢池中胆固醇可用性降低是导致VLDL分泌减少的一个因素。
