LOVASTATIN INDUCES SYNTHESIS OF CHOLESTEROL, WHICH ACTS AS A SECRETAGOGUE OF BILIARY PHOSPHOLIPIDS IN RATS

The effects of treatment with lovastatin (LS), a hypocholesterolemic d rug, 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 i n an aqueous milieu, we tested the hypothesis that excessive CH is sol ubilized and secreted into bile as cholesterol-phospholipid (CH-PL) ve sicles. 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 fo llowing. 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 adm inistration of [C-14]choline, a precursor of PC, [C-14]PC increased si gnificantly in bile. 3) Biliary output of PC increased twofold. 4) Qua si-elastic light scattering measurements of bile showed a 3.5-fold inc rease in intensity of the CH-PL vesicles, indicating higher concentrat ions of CH-PL vesicles, but there was no change in the intensity of th e micelles. These observations support the hypothesis that PC synthesi s was enhanced as a transport mechanism for secretion of the excessive amounts of cholesterol from the hepatocytes into bile as CH-PC vesicl es.