TMP-153, a novel ACAT inhibitor, lowers plasma cholesterol through its hepatic action in Golden hamsters

Abstract

The mechanism of the hypocholesterolemic action of N-[4-(2-chlorophenyl)-6,7-dimethyl-3-quinolyl]- N′-(2, 4-difluorophenyl) urea (TMP-153), a potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was studied in Golden hamsters. TMP-153 (0.5–1.5 mg/kg) dose-dependently reduced plasma total- and low density lipoprotein (LDL)-cholesterol without affecting high density lipoprotein (HDL)-cholesterol. TMP-153 markedly reduced the cholesterol influx into the plasma upon intravenous injection of Triton WR-1339. The compound also decreased cholesterol absorption calculated from dietary intake, biliary secretion and the absorption co-efficient. Hepatic cholesterol secretion was calculated by substracting the cholesterol absorption from the cholesterol influx. In hamsters, the liver accounted for 92% of the cholesterol influx with the remaining 8% coming from the intestine, and both were markedly decreased by TMP-153. Thus, it is likely that TMP-153 lowers plasma cholesterol through its hepatic action. In the liver, the compound significantly reduced the unesterified cholesterol content in addition to markedly reducing the content of esterified cholesterol. In accordance with this reduction, the half-life time of [ 125I]-LDL was significantly shortened by the compound, suggesting an increase in LDL receptors. However, the hepatic cholesterogenesis from [ 14C]acetate was decreased by TMP-153 treatment. This effect seems to be secondary, since the compound did not inhibit cholesterogenesis from [ 14C]acetate in HepG2 cells. From the data described above, the contribution of hepatic secretion and intestinal absorption of cholesterol to the plasma cholesterol level in Golden hamsters are discussed.