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
Dm. Peffley et Ak. Gayen, 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, Archives of biochemistry and biophysics, 337(2), 1997, pp. 251-260
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.