Role of cholesterol synthesis in regulation of bile acid synthesis and biliary cholesterol secretion in humans.
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.
Department of Medicine, VA Medical Center, Minneapolis, MN 55417.
J C
JC
Mitchell
B G
BG
Stone
G M
GM
Logan
W C
WC
Duane
D000368:Aged; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008148:Lovastatin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged
D001647:Bile Acids and Salts; D008078:Cholesterol, LDL; D002784:Cholesterol; D008148:Lovastatin