EFFECTS OF SIMVASTATIN ON THE METABOLISM OF POLYUNSATURATED FATTY-ACIDS AND ON GLYCEROLIPID, CHOLESTEROL, AND DE-NOVO LIPID-SYNTHESIS IN THP-1 CELLS

In the monocytic THP-I cells, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Cob) reductase inhibitor simvastatin (5 mu M) enhances the conv ersion of exogenous linoleic (18:2 n-6) and eicosapentaenoic (20:5 n-3 ) acids to their long-chain polyunsaturated fatty acid (LCPUFA) deriva tives, and this effect is associated with changes in the desaturation steps. In addition, formation of monounsaturated fatty acids from endo genously synthesized precursors is increased. These metabolic changes lead to elevated LC-PUFA and fatty acid (FA) unsaturation in cells. Th e effects of simvastatin on FA metabolism are associated with increase d synthesis of triglycerides from glycerol. The dose-effect relationsh ips for the activity of simvastatin on total linoleic acid (LA) conver sion and cholesterol synthesis reveal that enhancement of PUFA metabol ism is already maximal at 0.5 mu M simvastatin, whereas cholesterol sy nthesis is further inhibited by concentrations of simvastatin up to 5 mu M. The effects of 5 mu M simvastatin on PUFA metabolism are partial ly prevented by mevalonate (1 mM) and geranylgeraniol (5 mu M) but not by farnesol (10 mu M). These data indicate that HMG-CoA inhibitors ha ve profound effects on PUFA metabolism and that the pathways for chole sterol and PUFA synthesis are mutually modulated.