3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors unmask cryptic regulatory mechanisms.
The possibility that potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase may alter the mechanisms by which dietary cholesterol and farnesol regulate this gene was investigated by comparing the regulatory responses of rats maintained on diets with or without 0.04% Lovastatin supplementation to dietary cholesterol. It was found that the rate of hepatic HMG-CoA reductase transcription was significantly decreased by dietary cholesterol in animals fed Lovastatin-supplemented diets, whereas animals maintained on a normal chow diet showed no decrease in the rate of transcription. The levels of reductase mRNA were decreased to about 10% of controls in Lovastatin-supplemented animals in response to dietary cholesterol but not affected in nonsupplemented animals. Administration of farnesol, reputed to be the nonsterol regulator of reductase, to rats maintained on a diet containing Lovastatin decreased hepatic HMG-CoA reductase protein by 30% and the half-life of reductase immunoreactive protein to 4.0 h, which is close to that observed in chow-fed animals. In contrast, farnesol treatment does not affect the turnover rate of reductase protein in rats fed a normal chow diet. These results suggest that potent inhibitors of HMG-CoA reductase may unmask transcriptional regulation by dietary cholesterol and accelerated degradation of the reductase by the putative nonsterol regulator farnesol.
Lopez
D
D
Department of Biochemistry and Molecular Biology, College of Medicine, and Institute for Biomolecular Science, University of South Florida, Tampa 33612, USA.
Chambers
C M
CM
Ness
G C
GC
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases