Funatsu Toshiyuki, Kakuta Hirotoshi, Takasu Toshiyuki, Miyata Keiji
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co, Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 3058585, Japan.
Eur J Pharmacol. 2002 Nov 29;455(2-3):161-7. doi: 10.1016/s0014-2999(02)02611-0.
We investigated the effects of atorvastatin, a widely used 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and BMS-201038, a microsomal triglyceride transfer protein (MTP) inhibitor, in sucrose-fed hypertriglyceridemic rats to determine whether the activation of beta-oxidation by these compounds plays a role in their hypotriglyceridemic effect. The decrease in plasma triglyceride concentration and post-Triton very low-density lipoprotein (VLDL) triglyceride concentration, a measure of hepatic triglyceride secretion, by atorvastatin (30 mg/kg p.o.) for 2 weeks was to approximately the same degree as those by BMS-201038 (0.3 mg/kg). Atorvastatin (30 mg/kg) increased hepatic beta-oxidation activity by 54% (P < 0.01), while BMS-201038 (0.3 mg/kg) had no significant effect. Atorvastatin decreased hepatic triglyceride, fatty acid and cholesteryl ester concentrations by 21% to 39%, whereas BMS-201038 increased these variables by 28% to 307%. In the atorvastatin-treated groups, a significant relationship was seen not only between hepatic beta-oxidation activity and hepatic triglyceride concentration (R(2) = 0.535, P < 0.01), but also between hepatic and plasma triglyceride concentrations (R(2) = 0.586, P < 0.01). No effect of atorvastatin on hepatic fatty acid synthesis was observed. These results indicate that the activation of hepatic beta-oxidation by atorvastatin may contribute to the decrease in hepatic triglyceride concentration, leading to its hypotriglyceridemic effect.
我们研究了广泛使用的3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂阿托伐他汀和微粒体甘油三酯转移蛋白(MTP)抑制剂BMS-201038对蔗糖喂养的高甘油三酯血症大鼠的影响,以确定这些化合物激活β-氧化是否在其降甘油三酯作用中起作用。阿托伐他汀(30mg/kg口服)连续2周使血浆甘油三酯浓度和经曲拉通处理后的极低密度脂蛋白(VLDL)甘油三酯浓度(衡量肝脏甘油三酯分泌的指标)降低的程度,与BMS-201038(0.3mg/kg)大致相同。阿托伐他汀(30mg/kg)使肝脏β-氧化活性增加了54%(P<0.01),而BMS-201038(0.3mg/kg)没有显著影响。阿托伐他汀使肝脏甘油三酯、脂肪酸和胆固醇酯浓度降低了21%至39%,而BMS-201038使这些变量增加了28%至307%。在阿托伐他汀治疗组中,不仅肝脏β-氧化活性与肝脏甘油三酯浓度之间存在显著相关性(R²=0.535,P<0.01),而且肝脏与血浆甘油三酯浓度之间也存在显著相关性(R²=0.586,P<0.01)。未观察到阿托伐他汀对肝脏脂肪酸合成有影响。这些结果表明,阿托伐他汀激活肝脏β-氧化可能有助于降低肝脏甘油三酯浓度,从而产生其降甘油三酯作用。