INHIBITION OF SQUALENE SYNTHASE BUT NOT SQUALENE CYCLASE PREVENTS MEVALONATE-MEDIATED SUPPRESSION OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE SYNTHESIS AT A POSTTRANSCRIPTIONAL LEVEL

Previously, me found that mevalonate-derived products together with an oxysterol regulated reductase synthesis at a posttranscriptional leve l, To determine which products were responsible for this regulation, e ither the squalene synthase inhibitor zaragozic acid A or the squalene cyclase inhibitor 4,4,10-beta-trimethyl-trans-decal-3 beta-ol (TMD) w as added to lovastatin-treated Syrian hamster cells in conjunction wit h mevalonate, Mevalonate alone decreased reductase synthesis 50% compa red with lovastatin-treated cells, In contrast, when both zaragozic ac id A and mevalonate were added to lovastatin-treated cells, there was no change in reductase synthesis, With either treatment, reductase mRN A levels did not change compared with lovastatin-treated cells, When b oth 25-hydroxycholesterol and mevalonate were added to lovastatin-trea ted cells, reductase synthesis and mRNA levels were decreased 95 and 5 0%, respectively, The 10-fold difference between changes in reductase synthesis and mRNA levels under these conditions reflects a specific e ffect of mevalonate-derived isoprenoids on reductase synthesis at the translational level, In contrast, coincubation of cells with mevalonat e plus 25-hydroxycholesterol in the presence of zaragozic acid decreas ed reductase synthesis and mRNA levels 60 and 50%, respectively, compa red with lovastatin-treated cells, Moreover, degradation of reductase was increased approximately 7-fold in cells treated with mevalonate al one but only 3-fold in cells treated with mevalonate and zaragozic aci d A, These results indicate that isoprenoid products between mevalonat e and squalene affect reductase at a posttranslational level by increa sing degradation but do not regulate reductase synthesis at a posttran scriptional level, In contrast, when both TMD and mevalonate were adde d to lovastatin-treated cells, reductase synthesis was decreased appro ximately 50% with no corresponding decrease in reductase mRNA levels, similar to mevalonate only, Reductase degradation was increased approx imately 7-fold under these conditions, Cellular incubation in TMD, mev alonate, and 25-hydroxycholesterol decreased reductase synthesis and m RNA levels 95 and 50%, respectively, From these results we concluded t hat mevalonate-derived nonsterols synthesized between squalene and lan osterol decrease reductase synthesis at a translational level-either a lone or in combination with 25-hydroxycholesterol-and also increase re ductase degradation, (C) 1997 Academic Press.