REGULATION OF EARLY CHOLESTEROL-BIOSYNTHESIS IN RAT-LIVER - EFFECTS OF STEROLS, BILE-ACIDS, LOVASTATIN, AND BM-15.766 ON 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A SYNTHASE AND ACETOACETYL COENZYME-A THIOLASE ACTIVITIES

Cytosolic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase cat alyzes the formation of HMG-CoA, the substrate for the rate-controllin g enzyme in the cholesterol biosynthetic pathway. To explore the regul ation in liver, we developed a new, accurate, and reliable reversed-ph ase ion-pair chromatographic assay that uses nonradioactive substrates and n-propionyl coenzyme A as an internal recovery standard. The hepa tic activities were measured in rats treated with cholesterol, sitoste rol, cholic acid, deoxycholic acid, ursodeoxycholic acid, cholestyrami ne, bile fistula, lovastatin, and BM 15.766, an inhibitor of 7-dehydro cholesterol Delta(7)-reductase, and were compared with microsomal HMG- CoA reductase and cytosolic acetoacetyl coenzyme A (AcAc-CoA) thiolase activities. HMG-CoA synthase activity was effectively suppressed in s ynchrony with HMG-CoA reductase activity by treatments with cholestero l (-41%, P <.05), cholic acid (-72%, P <.005), and deoxycholic acid (- 62%, P <.05). However, ursodeoxycholic acid increased activity 84% (P <.05) and intravenous sitosterol did not change activity. AcAc-CoA thi olase activities also paralleled HMG-CoA reductase and HMG-CoA synthas e activities, but differences were not statistically significant. In c ontrast to inhibition, up-regulation of hepatic HMG-CoA synthase activ ities by cholestyramine, bile fistula, and lovastatin was much less th an HMG-CoA reductase activities. In addition, BM 15.766 did not stimul ate synthase activity, whereas lovastatin increased activity 2.4-fold. Thus, hepatic HMG-CoA synthase activity was regulated coordinately wi th HMG-CoA reductase, and responded more forcefully to regulatory stim uli than acetoacetyl-CoA thiolase activity but usually less than HMG-C oA reductase.