Risé P, Colombo C, Galli C
Institute of Pharmacological Sciences, University of Milan, Milano, Italy.
J Lipid Res. 1997 Jul;38(7):1299-307.
In the monocytic THP-1 cells, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin (5 microM) enhances the conversion of exogenous linoleic (18:2 n-6) and eicosapentaenoic (20:5 n-3) acids to their long-chain polyunsaturated fatty acid (LC-PUFA) derivatives, and this effect is associated with changes in the desaturation steps. In addition, formation of monounsaturated fatty acids from endogenously synthesized precursors is increased. These metabolic changes lead to elevated LC-PUFA and fatty acid (FA) unsaturation in cells. The effects of simvastatin on FA metabolism are associated with increased synthesis of triglycerides from glycerol. The dose-effect relationships for the activity of simvastatin on total linoleic acid (LA) conversion and cholesterol synthesis reveal that enhancement of PUFA metabolism is already maximal at 0.5 microM simvastatin, whereas cholesterol synthesis is further inhibited by concentrations of simvastatin up to 5 microM. The effects of 5 microM simvastatin on PUFA metabolism are partially prevented by mevalonate (1 mM) and geranylgeraniol (5 microM) but not by farnesol (10 microM). These data indicate that HMG-CoA inhibitors have profound effects on PUFA metabolism, and that the pathways for cholesterol and PUFA synthesis are mutually modulated.
在单核细胞THP-1细胞中，3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂辛伐他汀（5微摩尔）可增强外源性亚油酸（18:2 n-6）和二十碳五烯酸（20:5 n-3）向其长链多不饱和脂肪酸（LC-PUFA）衍生物的转化，且这种作用与去饱和步骤的变化有关。此外，内源性合成前体生成单不饱和脂肪酸的过程增加。这些代谢变化导致细胞中LC-PUFA和脂肪酸（FA）不饱和度升高。辛伐他汀对FA代谢的影响与甘油三酯从甘油合成的增加有关。辛伐他汀对总亚油酸（LA）转化和胆固醇合成活性的剂量-效应关系表明，在0.5微摩尔辛伐他汀时PUFA代谢的增强已达到最大值，而高达5微摩尔的辛伐他汀浓度可进一步抑制胆固醇合成。5微摩尔辛伐他汀对PUFA代谢的影响部分被甲羟戊酸（1毫摩尔）和香叶基香叶醇（5微摩尔）阻断，但未被法呢醇（10微摩尔）阻断。这些数据表明，HMG-CoA抑制剂对PUFA代谢有深远影响，且胆固醇和PUFA合成途径相互调节。
