ABSTRACT
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.
