title: Plant-derived monoterpenes suppress hamster kidney cell 3-hydroxy-3-methylglutaryl coenzyme a reductase synthesis at the post-transcriptional level.
abstract: The rate-limiting enzyme for mevalonate and cholesterol synthesis in mammalian cells is 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Control occurs through both transcriptional and post-transcriptional actions signaled by the end product, cholesterol, and by isoprenoid intermediates. End products of plant mevalonate metabolism, i.e., plant-derived isoprenoids, also suppress mammalian HMG-CoA reductase. Previous studies reported that isoprenoids suppress reductase synthesis at a post-transcriptional level. We tested the hypothesis that plant-derived isoprenoids also regulate mammalian HMG-CoA reductase synthesis at a post-transcriptional level by incubating lovastatin-treated C100 cells with mevalonate or a plant-derived isoprenoid (the monoterpenes, limonene, perillyl alcohol or geraniol) either alone or combined with the oxysterol, 25-hydroxycholesterol (25-OH C). Mevalonate decreased HMG-CoA reductase synthesis and mRNA levels by 65 and 66%, respectively (P < 0.05). The cyclic monoterpenes, limonene and perillyl alcohol, lowered HMG-CoA reductase synthesis by 70 and 89%, respectively (P < 0.05); although neither reduced HMG-CoA reductase mRNA levels (P = 0.88). Geraniol, an acyclic monoterpene, suppressed HMG-CoA reductase synthesis by 98% and lowered mRNA levels by 66% (P < 0.05). A combination of 25-OH C and either mevalonate or any three monoterpenes reduced HMG-CoA reductase mRNA levels (P < 0.05) compared with lovastatin-only treated cells. However, the dual combination of 25-OH C and either mevalonate or a monoterpene resulted in a greater decrease in HMG-CoA reductase synthesis than in mRNA levels. The difference between changes in HMG-CoA reductase synthesis and mRNA levels reflects a specific effect of isoprenoids on HMG-CoA reductase synthesis at the translational level. Mevalonate enhanced HMG-CoA reductase degradation, but no such effect was observed for the monoterpenes. These results indicate that the three plant-derived isoprenoids primarily suppress HMG-CoA reductase synthesis at a post-transcriptional level by attenuating HMG-CoA reductase mRNA translational efficiency.
authors.affiliation: Dennis M. Peffley, University of Health Sciences, Department of Biochemistry, Kansas City, MO 64106-1453, USA. dpeffley@uhs.edu
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Peffley
authors.forename: Apurba K
authors.initials: AK
authors.lastname: Gayen
mesh_terms: D000818:Animals; D001345:Autoradiography; D002478:Cells, Cultured; D006224:Cricetinae; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008647:Mesocricetus; D008798:Mevalonic Acid / Q000494:pharmacology*; D008967:Molecular Biology; D039821:Monoterpenes / Q000494:pharmacology*; D010936:Plant Extracts; D012313:RNA / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D039821:Monoterpenes; D010936:Plant Extracts; D012313:RNA; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid