Effect of SMP-500, a novel ACAT inhibitor, on hepatic cholesterol disposition in rats.

The effects of SMP-500, a novel ACAT inhibitor, on serum lipid levels, hepatic lipid secretion rate, and hepatic lipid disposition in rats were studied to clarify its lipid-lowering action. SMP-500 reduced the serum cholesterol level in a dose-dependent manner in rats fed a hypercholesterolemic diet. SMP-500 also reduced hepatic free cholesterol content in addition to hepatic total and esterified cholesterol contents. Biliary concentrations of cholesterol and bile acid were increased by SMP-500; however, the bile flow and lithogenic index were not affected. SMP-500 increased cholesterol 7a-hydroxylase mRNA level. Therefore, it is suggested that the increase in concentrations of cholesterol and bile acid in bile is due to both the increase of bile acid production through the increase of cholesterol 7alpha-hydroxylase and the decrease of hepatic free cholesterol content. An inhibitory effect of SMP-500 both on the cholesterol secretion and on the TG secretion from liver was observed. SMP-500 reduced the serum TG level in sucrose-fed rats. From these results, one may hypothesize that the suppression of hepatic VLDL secretion probably plays an important role on both cholesterol- and TG-lowering effects of SMP-500.