Sterol regulatory element binding protein-mediated effect of fluvastatin on cytosolic 3-hydroxy-3-methylglutaryl-coenzyme A synthase transcription

The effects of acute treatment with fluvastatin, a hypocholesteremic drug, on the mRNA levels of several regulatory enzymes of cholesterogenesis and o f the LDL receptor were determined in rat liver. Fluvastatin increased the hepatic mRNA levels for HMG-CoA reductase up to la-fold in 5 weeks of treat ment at a daily dose of 6.3 mg/kg. The effect was less marked in cytosolic HMG-CoA synthase, farnesyl-PP synthase, squalene synthetase, and LDL recept or. SREBP-9 mRNA levels were also increased, but SREBP-1 were not. De novo synthesis of cholesterol in several cultured cells was reduced by increasin g concentrations of fluvastatin, and the IC50 values of fluvastatin in HepG 2, CV-1, and CHO cells were respectively 0.01, 0.05, and 0.1 mu M. When CHO cells stably transfected with a chimeric gene composed of the promoter of cytosolic HMG-CoA synthase and the CAT gene as a reporter were incubated wi th fluvastatin, the CAT gene was overexpressed, an effect which was similar to the cotransfection with the processed form of SREBP-1a, Both ALLN and f luvastatin increased the transcriptional activity of cytosolic HMG-CoA synt hase. Mutation in either SRE or NF-Y boxes abolished the increase in transc riptional rate caused by fluvastatin in the promoter of cytosolic HMG-CoA s ynthase, These results indicate that the increase in transcriptional activi ty in the HMG-CoA synthase gene attributable to fluvastatin is a consequenc e of the activation of the proteolytic cleavage of SREBPs by reduced levels of intracellular cholesterol. (C) 2000 Academic Press.