Lovastatin increases arachidonic acid levels and stimulates thromboxane synthesis in human liver and monocytic cell lines.
The effect of lovastatin (LOV), the inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, on linoleic acid (LA, 18:2n-6) metabolism was examined in human monocytic Mono Mac 6 (MM6) and hepatoma Hep G2 cells. The desaturation of LA was examined after LOV (72 h, 10 microM) or dimethylsulfoxide (LOV carrier, < 0.1%) and [14C]LA (last 18 h, 0.3 microCi, 5 microM). In both cell lines, LOV reduced the percentage of 14C label associated with LA and increased the percentage of label in the 20:4n-6 and the 22:5n-6 fractions. In Hep G2 but not MM6 cells, this effect was fully reversible by means of coincubation with mevalonic acid (500 microM), but not with cholesterol or lipoproteins. In both cell lines, the LOV-mediated increase in LA desaturation resulted in dose-dependent reductions of LA and elevations of AA in cellular phospholipids. The lipids secreted by LOV-treated Hep G2 cells were also enriched in arachidonic acid (AA). In the MM6 cells, LOV increased release of thromboxane upon stimulation with the calcium ionophore A23187. In summary, our findings of higher LA desaturation and AA enrichment of lipids secreted by the Hep G2 cells suggest that LOV treatment may increase the delivery of AA from the liver to extrahepatic tissues. The changes in membrane fatty acid composition can influence a variety of cellular functions, such as eicosanoid synthesis in monocytic cells. The mechanism appears to be related to the reduced availability of intermediates of cholesterogenesis.
Hrboticky
N
N
Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Universität München, Germany.
Tang
L
L
Zimmer
B
B
Lux
I
I
Weber
P C
PC
D000704:Analysis of Variance; D016718:Arachidonic Acid / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D005227:Fatty Acids / Q000032:analysis; D006801:Humans; D007700:Kinetics; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms; D008148:Lovastatin / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D013931:Thromboxanes / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002788:Cholesterol Esters; D005227:Fatty Acids; D008041:Linoleic Acids; D010743:Phospholipids; D013931:Thromboxanes; D014280:Triglycerides; D016718:Arachidonic Acid; D002784:Cholesterol; D019787:Linoleic Acid; D008148:Lovastatin