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-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase gene expression was investigated by measuring mRNA, protein, and enzyme activity in rats fed cholesterol or given drugs that deplete both endogenous sterols and nonsterols or that selectively deplete sterols. It was found that while dietary cholesterol had little effect on HMG-CoA reductase mRNA levels; immunoreactive protein was reduced to barely detectable levels, as was enzyme activity. Any possible effect on catalytic efficiency is thus ruled out. When rats were fed diets containing Lovastatin, a potent HMG-CoA reductase inhibitor which blocks synthesis of both nonsterols and sterols, similar 15- to 20-fold increases were observed for both HMG-CoA reductase mRNA and activity. However, HMG-CoA reductase immunoreactive protein was increased more than 200-fold. When endogenous sterols were selectively depleted by inhibiting squalene synthase with Zargozic acid A, the increase observed in reductase mRNA was similar to that seen in immunoreactive protein and enzyme activity. This is consistent 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, sterols likely act at the level of mRNA while nonsterols exert their regulatory effects at the level of HMG-CoA reductase protein. (C) 1994 Academic Press, Inc.