THE EFFECTS OF CLOFIBRATE AND BEZAFIBRATE ON CHOLESTEROL-METABOLISM IN THE LIVER OF THE MALE-RAT

Fibric acid derivatives are used to treat hyperlipidemia and have wide ranging effects on lipid metabolism. The action of these compounds on cholesterol esterification, catalyzed by acyl coenzyme A:cholesterol acyltransferase (ACAT), has been quite widely studied, but their effec t on cholesteryl ester hydrolysis and the enzyme neutral cholesteryl e ster hydrolase (nCEH) has been largely ignored. Male rats were therefo re fed for 10 d on a standard chow diet supplemented with either clofi brate or bezafibrate, to study their effects on plasma lipid levels an d hepatic cholesterol metabolism. Plasma triacylglycerols were not sig nificantly altered by these diets, but bezafibrate significantly lower ed plasma cholesterol levels (29.7%, P < 0.01). When expressed per uni t weight of DNA, both fibrates reduced the hepatic content of triacylg lycerol, cholesterol and cholesteryl esters (40, 18.7, 16.5 and 66.7, 28.6, 34.2% for clofibrate and bezafibrate, respectively). ACAT activi ty was significantly reduced by both drugs, but clofibrate (65% inhibi tion) was more effective than bezafibrate (35% inhibition). The most d ramatic effect of the diets was a marked increase in;the activity of b oth the microsomal and the cytosolic nCEH. When expressed on a whole l iver basis, the effect of bezafibrate on the cytosolic enzyme (13.6-fo ld increase in activity) was much greater than that of clofibrate (4.8 -fold increase). Increases in the activity of a cytosolic protein that inhibits the activity of nCEH were also noted, but these changes were relatively small. The results suggest that the activation of nCEH, in combination with the inhibition in ACAT activity, contributes to a de crease in the cholesteryl ester content of the liver which may influen ce the secretion of very low density lipoprotein.