Risé P, Ghezzi S, Levati M G, Mirtini R, Colombo C, Galli C
Department of Pharmacological Sciences, University of Milan, 20133 Milano, Italy.
Lipids. 2003 Aug;38(8):841-6. doi: 10.1007/s11745-003-1134-5.
In THP-1 cells, simvastatin decreases, in a concentration-dependent manner, cholesterol synthesis and increases linoleic acid (LA) conversion to its long-chain derivatives, in particular to arachidonic acid, activating delta6 and delta5 fatty acid (FA) desaturases. The intermediates in cholesterol synthesis, mevalonate and geranylgeraniol, partially reverse the effects of simvastatin on the LA conversion. The aims of this work were to evaluate: (i) the correlation between cholesterol synthesis and desaturase activity and (ii) the possible involvement of protein isoprenylation in desaturase activity, assessed through pharmacological treatments. THP-1 cells were incubated with [1-14C]LA or with [1-14C]di-homo-gamma-linolenic acid (DHGLA) and treated with simvastatin or with curcumin and nicardipine, inhibitors of desaturases. Curcumin was more active than nicardipine in inhibiting LA and DHGLA conversion: 20 microM curcumin, alone or with simvastatin, totally inhibited delta6 and delta5 desaturation steps; 10 microM nicardipine only partially inhibited the enzymes, being more active on delta5 desaturase. Simvastatin treatment decreased the incorporation of acetate in cholesterol (-93.8%) and cholesterol esters (-70.2%), as expected. Curcumin and nicardipine also decreased cholesterol synthesis and potentiated simvastatin. Finally, the isoprenylation inhibitors (perillic acid and GGTI-286) neither affected the conversion of LA nor inhibited the delta5 desaturase activity. In conclusion, our results indicate that there is no direct relationship between cholesterol synthesis and desaturase activity. In fact, simvastatin decreased cholesterol synthesis and enhanced LA conversion (mainly delta5 desaturation), whereas curcumin and nicardipin decreased delta5 desaturation, with a limited effect on cholesterol synthesis.
在THP-1细胞中，辛伐他汀以浓度依赖性方式降低胆固醇合成，并增加亚油酸（LA）向其长链衍生物的转化，尤其是向花生四烯酸的转化，从而激活δ6和δ5脂肪酸（FA）去饱和酶。胆固醇合成的中间体甲羟戊酸和香叶基香叶醇可部分逆转辛伐他汀对LA转化的影响。本研究的目的是评估：（i）胆固醇合成与去饱和酶活性之间的相关性；（ii）通过药理学处理评估蛋白质异戊二烯化在去饱和酶活性中可能的作用。将THP-1细胞与[1-14C]LA或[1-14C]二高-γ-亚麻酸（DHGLA）一起孵育，并用辛伐他汀或姜黄素和尼卡地平（去饱和酶抑制剂）进行处理。姜黄素在抑制LA和DHGLA转化方面比尼卡地平更有效：20μM姜黄素单独使用或与辛伐他汀联合使用时，完全抑制δ6和δ5去饱和步骤；10μM尼卡地平仅部分抑制这些酶，对δ5去饱和酶的活性更强。如预期的那样，辛伐他汀处理降低了乙酸盐掺入胆固醇（-93.8%）和胆固醇酯（-70.2%）的水平。姜黄素和尼卡地平也降低了胆固醇合成并增强了辛伐他汀的作用。最后，异戊二烯化抑制剂（紫苏酸和GGTI-286）既不影响LA的转化，也不抑制δ5去饱和酶活性。总之，我们的结果表明胆固醇合成与去饱和酶活性之间没有直接关系。事实上，辛伐他汀降低了胆固醇合成并增强了LA转化（主要是δ5去饱和），而姜黄素和尼卡地平降低了δ5去饱和，对胆固醇合成的影响有限。
