alpha-linolenic acid reduces the lovastatin-induced rise in arachidonic acid and elevates cellular lipoprotein eicosapentaenoic and docosahexaenoic acid levels in Hep G2 cells

Increased plasma arachidonic acid (20:4 omega 6) levels have been reported in patients undergoing 3-hydroxy-3-methyl coenzyme A (HMG-CoA) reductase inhibitor therapy. We have previously shown that this effect is related to an increased conversion of linoleic acid (18:2 omega 6) to 20:4 omega 6 via the fatty acid desaturases and results in an increased formation of biologically potent eicosanoids. Because fatty acid desaturases also act on of fatty acids, and because the long chain omega 3 fatty acids counterbalance many of the physiological effects of omega 6 fatty acids, we now examine the effects of alpha-linolenic acid (18:3 omega 3) supplementation on the lovastatin-induced changes in cellular and lipoprotein fatty acid levels. Human hepatoma Hep G2 cells were incubated with lovastatin (10 mu mol/L) or its carrier dimethyl sulphoxide (DMSO, final concentration 0.1%) for 72 hr and with albumin-bound 18:3 omega 3 (40 mu mol/L) alone or with different ratios of 18:3 omega 3 to 18:2 omega 6 for the last 24 hr. In comparison with control cells, lovastatin-treated cells converted more 18:3 omega 3 into eicosapentaenoic (20:5 omega 3) and docosahexaenoic (22:6 omega 3) acids, which were incorporated in increasing amounts in cellular phospholipids and lipids secreted by these cells. The lovastatin-mediated increase in 20:4 omega 6 levels in cellular and secreted lipids was also significantly reduced in 18:3 omega 3-supplemented cells. The effect of 18:3 omega 3 supplementation on the lovastatin-induced changes in omega 6 and omega 3 fatty acid composition was dependent on the 18:3 omega 3/18:2 omega 6 supplementation ratio. The present studies suggest that the previously described effects of HMGCoA reductase inhibitors on polyunsaturated fatty acid metabolism can be modulated by the dietary 18:3 omega 3/18:2 omega 6 ratio.