AJP - Gastrointestinal and Liver Physiology, Vol 268, Issue 2 242-G250, Copyright © 1995 by American Physiological Society
Lovastatin induces synthesis of cholesterol, which acts as a secretagogue of biliary phospholipids in rats
W. G. Linscheer, B. Atreyee, K. M. Uma, W. John, N. Sandor and N. Jyotirmoy
Department of Medicine, Veterans Affairs Medical Center, Syracuse, New York.
The effects of treatment with lovastatin (LS), a hypocholesterolemic drug,
on hepatic metabolism of cholesterol (CH) and phosphatidylcholine (PC) were
studied in rats. Hepatic synthesis of CH was increased, as previously
reported by our laboratory. Total plasma CH was increased, and biliary
secretion of CH was raised fourfold, but biliary secretion of bile salts
was not affected. Because CH is practically insoluble in an aqueous milieu,
we tested the hypothesis that excessive CH is solubilized and secreted into
bile as cholesterol-phospholipid (CH-PL) vesicles. The effects of
LS-induced increase in CH synthesis on hepatic metabolism of PC after 7
days of oral LS treatment (17.5 mg/day) were studied. Our results showed
accelerated synthesis of PC and increased biliary secretion of newly formed
PC into bile, as evidenced by the following. 1) Phosphocholine
cytidylyltransferase (EC 2.7.7.15) activity, the rate limiting enzyme in
the synthesis of PC, increased 2.5-fold in the hepatic microsomes of the
hepatocytes. 2) After intravenous administration of [14C]choline, a
precursor of PC, [14C]PC increased significantly in bile. 3) Biliary output
of PC increased twofold. 4) Quasi-elastic light scattering measurements of
bile showed a 3.5-fold increase in intensity of the CH-PL vesicles,
indicating higher concentrations of CH-PL vesicles, but there was no change
in the intensity of the micelles. These observations support the hypothesis
that PC synthesis was enhanced as a transport mechanism for secretion of
the excessive amounts of cholesterol from the hepatocytes into bile as
CH-PC vesicles.
