Journal of Lipid Research, Vol 32, 1143-1149, Copyright © 1991 by Lipid Research, Inc.
Role of cholesterol synthesis in regulation of bile acid synthesis and biliary cholesterol secretion in humans
JC Mitchell, BG Stone, GM Logan and WC Duane
Department of Medicine, VA Medical Center, Minneapolis, MN 55417.
We used lovastatin, a specific inhibitor of HMG-CoA reductase, to study the
role of cholesterol synthesis in regulation of both bile acid synthesis,
measured by release of 14CO2 from [26-14C]cholesterol, and biliary
cholesterol secretion, measured by standard marked perfusion techniques, in
humans. Six volunteers were studied in each of four periods: a) control; b)
6-10 hours after a single 40 mg oral dose of lovastatin to study acute
effects; c) after 5-6 weeks of lovastatin 40 mg orally twice a day to study
steady-state effects; and d) 24 h after cessation of chronic lovastatin.
Mean bile acid synthesis fell to 69% of control (P less than 0.01) after
single-dose lovastatin and remained at 83% of control after 5-6 weeks on
lovastatin (P less than 0.05). After withdrawal of lovastatin, mean bile
acid synthesis was 88% of control (NS). Mean biliary cholesterol secretion
did not change after single-dose lovastatin (103% of control), but fell to
81% of control during chronic lovastatin treatment (P less than 0.05).
After withdrawal of lovastatin, mean cholesterol secretion remained at 80%
of control (P less than 0.05). These data suggest that in humans
cholesterol synthesis is an immediate regulator of bile acid synthesis.
Cholesterol synthesis also regulates biliary cholesterol secretion, but the
effect is not immediate and therefore may be indirect.
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