REGULATION OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE GENE-EXPRESSION BY STEROLS AND NONSTEROLS IN RAT-LIVER

The mechanisms by which sterols and nonsterols regulate hepatic 3-hydr oxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase gene expression wa s investigated by measuring mRNA, protein, and enzyme activity in rats fed cholesterol or given drugs that deplete both endogenous sterols a nd nonsterols or that selectively deplete sterols. It was found that w hile dietary cholesterol had little effect on HMG-CoA reductase mRNA l evels; immunoreactive protein was reduced to barely detectable levels, as was enzyme activity. Any possible effect on catalytic efficiency i s thus ruled out. When rats were fed diets containing Lovastatin, a po tent HMG-CoA reductase inhibitor which blocks synthesis of both nonste rols and sterols, similar 15- to 20-fold increases were observed for b oth HMG-CoA reductase mRNA and activity. However, HMG-CoA reductase im munoreactive protein was increased more than 200-fold. When endogenous sterols were selectively depleted by inhibiting squalene synthase wit h Zargozic acid A, the increase observed in reductase mRNA was similar to that seen in immunoreactive protein and enzyme activity. This is c onsistent with the concept that endogenous sterols exert their effects at the level of transcription while endogenous nonsterols act at the level of translation. The results suggest that in whole animals, stero ls likely act at the level of mRNA while nonsterols exert their regula tory effects at the level of HMG-CoA reductase protein. (C) 1994 Acade mic Press, Inc.