INCREASED CELLULAR TRIGLYCERIDE LEVELS IN HUMAN MONOCYTIC AND RAT SMOOTH-MUSCLE CELLS AFTER LOVASTATIN

beta-Hydroxy-Beta-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhib itors reduce plasma LDL cholesterol by upregulating hepatic LDL recept ors. However, their effects on lipid metabolism in extrahepatic cells may also contribute to their therapeutic benefit. We examined the effe cts of lovastatin (LOV) on cellular lipid levels in the human monocyti c Mono Mac 6sr and cultured rat smooth muscle cells. In both cell type s, LOV produced a dose-dependent increase in cellular triglycerides. T his increase was observed in cells grown in the absence of exogenous l ipids in the culture medium, but was more pronounced after additions o f oleic acid (50 to 200 mu M) and VLDL (50 to 200 mu g ml(-1)). In Mon o 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 lipoprot ein-replete medium, the LOV-induced rise in triglycerides did not corr elate with cellular cholesterol. LOValso reduced cellular cholesterol esterification and increased the synthesis of fatty acids and their in corporation into triglycerides and phospholipids. Increased triglyceri de levels were also seen in Mono Mac 6sr cells treated with the lanost erol demethylase inhibitor RS-21607 and the acylcoenzyme A:cholesterol acyltransferase inhibitor SaH 58035. Our findings suggest that the LO V-induced triglyceride accumulation involves changes in intracellular cholesterol pools regulating cellular fatty acid concentrations. Altho ugh decreased cholesterol levels in cells participating in plaque form ation are beneficial, the impact of the herein described shift in intr acellular neutral lipid metabolism on other cellular functions warrant s further investigation. (C) 1997 Elsevier Science B.V.