In the chronic bile
fistula rat, the administration of a bolus dose of
mevinolinic acid, an inhibitor of
HMG-CoA reductase, was followed by rapid down-regulation of
cholesterol 7 alpha-hydroxylase activity and a decrease in
bile acid synthesis. These observations suggested that either newly synthesized
cholesterol or some other metabolite of
mevalonate may be involved in the regulation of
bile acid synthesis. In order to distinguish between these two alternatives, we carried out experiments in which
cholesterol synthesis was blocked by
AY9944, a compound that inhibits the conversion of
7-dehydrocholesterol to
cholesterol, a last step in the
cholesterol biosynthesis pathway. Rats underwent biliary diversion for 72 h at which time they were given intravenously either a bolus dose of
AY9944 (1 mg/kg) or control vehicle. At 0 (pre-treatment control), 0.5, 1.5, and 3 h post bolus, livers were harvested and specific activities of
cholesterol 7 alpha-hydroxylase were determined. At 1.5, 3, and 6 h post bolus,
AY9944 inhibited
bile acid synthesis by 19 +/- 6%, 40 +/- 4%, and 41 +/- 6%, respectively, as compared to pretreatment baseline.
Cholesterol 7 alpha-hydroxylase activity determined at 0.5, 1.5, and 3 h was decreased by 44 +/- 6%, 44 +/- 2%, and 36 +/- 2%, respectively, as compared to the control value. In in vitro experiments using microsomes from livers of control bile
fistula rats, the addition of
AY9944 (up to 100 microM) failed to inhibit
cholesterol 7 alpha-hydroxylase activity. The results of this study demonstrate that, in the chronic bile
fistula rat, acute inhibition of
cholesterol synthesis at either early or late steps leads to a rapid down-regulation of
cholesterol 7 alpha-hydroxylase activity and decrease in
bile acid synthesis.