EFFECT OF SQUALENE SYNTHASE INHIBITION ON THE EXPRESSION OF HEPATIC CHOLESTEROL BIOSYNTHETIC-ENZYMES, LDL RECEPTOR, AND CHOLESTEROL 7-ALPHAHYDROXYLASE

Squalene synthase catalyzes the committed step in the biosynthesis of sterols. Treating rats with zaragozic acid A, a potent inhibitor of sq ualene synthase, caused marked increases in hepatic 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) synthase, HMG-CoA reductase, squalene sy nthase, and LDL receptor mRNA levels. The increase in HMG-CoA reductas e mRNA fully accounted for the increases seen in enzyme protein and ac tivity. Farnesyl pyrophosphate synthase mRNA and activity were only sl ightly increased by zaragozic acid A, while cholesterol 7 alpha hydrox ylase mRNA levels were decreased substantially. When rats were pretrea ted with zaragozic acid A, there was no change in mRNA levels for the cholesterol. biosynthetic enzymes or cholesterol 7 alpha hydroxylase u pon subsequent treatment with mevalonolactone. Under these same condit ions, the enzymatic activity of HMG-CoA reductase was also unaffected. Mevalonolactone treatment reduced the zaragozic acid A-mediated incre ase in hepatic LDL receptor mRNA levels. Feeding cholesterol eliminate d the zaragozic acid A-induced increase in HMG-CoA reductase mRNA leve ls. These results suggest that inhibition of squalene synthase decreas es the level of a squalene-derived regulatory product, resulting in al tered amounts of several mRNAs and coordinate increases in HMG-CoA red uctase mRNA, protein, and activity. The increase in HMG-CoA reductase gene expression was closely related to the degree of inhibition of cho lesterol synthesis caused by zaragozic acid A. (C) 1994 Academic Press ,Inc.