Hrboticky N, Becker A, Kruse H J, Weber P C
Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians Universität, München, Germany.
Biochim Biophys Acta. 1997 Nov 30;1349(3):211-21. doi: 10.1016/s0005-2760(97)00136-7.
Beta-hydroxy-beta-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors reduce plasma LDL cholesterol by upregulating hepatic LDL receptors. However, their effects on lipid metabolism in extrahepatic cells may also contribute to their therapeutic benefit. We examined the effects of lovastatin (LOV) on cellular lipid levels in the human monocytic Mono Mac 6sr and cultured rat smooth muscle cells. In both cell types, LOV produced a dose-dependent increase in cellular triglycerides. This increase was observed in cells grown in the absence of exogenous lipids in the culture medium, but was more pronounced after additions of oleic acid (50 to 200 microM) and VLDL (50 to 200 microg ml-1). In Mono Mac 6sr cells grown in medium containing 10% delipidated FCS for the last 16 h, the LOV-induced rise in triglyceride levels was completely reversed by 2 mM mevalonic acid and was associated with a decrease in cellular cholesterol. However, when cells were maintained in lipoprotein-replete medium, the LOV-induced rise in triglycerides did not correlate with cellular cholesterol. LOV also reduced cellular cholesterol esterification and increased the synthesis of fatty acids and their incorporation into triglycerides and phospholipids. Increased triglyceride levels were also seen in Mono Mac 6sr cells treated with the lanosterol demethylase inhibitor RS-21607 and the acylcoenzyme A:cholesterol acyltransferase inhibitor SaH 58035. Our findings suggest that the LOV-induced triglyceride accumulation involves changes in intracellular cholesterol pools regulating cellular fatty acid concentrations. Although decreased cholesterol levels in cells participating in plaque formation are beneficial, the impact of the herein described shift in intracellular neutral lipid metabolism on other cellular functions warrants further investigation.
β-羟基-β-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂通过上调肝脏低密度脂蛋白（LDL）受体来降低血浆LDL胆固醇水平。然而，它们对肝外细胞脂质代谢的影响也可能有助于其治疗益处。我们研究了洛伐他汀（LOV）对人单核细胞Mono Mac 6sr和培养的大鼠平滑肌细胞中细胞脂质水平的影响。在这两种细胞类型中，LOV均导致细胞甘油三酯呈剂量依赖性增加。在无外源性脂质的培养基中生长的细胞中观察到了这种增加，但在添加油酸（50至200微摩尔）和极低密度脂蛋白（VLDL，50至200微克/毫升）后更为明显。在最后16小时在含10%脱脂胎牛血清（FCS）的培养基中生长的Mono Mac 6sr细胞中，2毫摩尔甲羟戊酸完全逆转了LOV诱导的甘油三酯水平升高，且这与细胞胆固醇降低有关。然而，当细胞维持在富含脂蛋白的培养基中时，LOV诱导的甘油三酯升高与细胞胆固醇无关。LOV还降低了细胞胆固醇酯化，并增加了脂肪酸的合成及其掺入甘油三酯和磷脂中。用羊毛甾醇脱甲基酶抑制剂RS-21607和酰基辅酶A：胆固醇酰基转移酶抑制剂SaH 58035处理的Mono Mac 6sr细胞中也观察到甘油三酯水平升高。我们的研究结果表明，LOV诱导的甘油三酯积累涉及调节细胞脂肪酸浓度的细胞内胆固醇池的变化。虽然参与斑块形成的细胞中胆固醇水平降低是有益的，但本文所述的细胞内中性脂质代谢变化对其他细胞功能的影响值得进一步研究。
