CORRECTION OF DYSLIPOPROTEINEMIA OF CASEIN-FED RABBIT BY FCE-27677, APOTENT NOVEL ACAT INHIBITOR

Rabbits fed a wheat starch casein diet develop hypercholesterolaemia c haracterized by the plasma elevation of low density lipoprotein (LDL) that is caused by oversecretion of apoB-100 containing lipoproteins by the liver and by the suppression of the EDTA-sensitive hepatic beta- very low density lipoprotein (VLDL)-LDL receptor. In this study, the e ffect of FCE 27677 aminophenyl)4,5-dimethyl-dioxolan-2-yl]methylurea) a novel potent systemic acylCoA:cholesterol acetyltransferase (ACAT, E C 2.3.1.26) inhibitor, has been evaluated. When New Zealand White rabb its were fed with casein for 4 weeks, LDL cholesterol increased from 1 4+/-3 mg/dl(-1) to 77+/-6 mg/dl(-1). By contrast the animals receiving FCE 27677 (10 mg kg(-1) d(-1)) mixed with the casein diet maintained a normal LDL concentration (22+/-3 mg dl(-1)). This hypolipidaemic eff ect was also observed when rabbits previously made hypercholesterolaem ic by being fed casein for 4 weeks were then treated for a month with FCE 27677. [I-125]LDL plasma turnover studies and [I-125]LDL binding s tudies to liver membranes were carried out with the purpose of investi gating the mechanism of action of the drug. The LDL apoB-100 productio n rate in chow-fed, casein-fed, and casein-fed rabbits receiving FCE 2 7677, was respectively 10.5, 22.4, and 12.5 mg kg(-1) d(-1). The turno ver rate of [I-125]LDL in the animals receiving the drug was not, howe ver, different from that in the rabbits fed the casein diet alone (2.3 81 vs 2.079 pools d(-1)). Both values were lower than that in chow-fed animals (3.271 pools d(-1)). FCE 27677 did not normalize the activity of the hepatic beta-VLDL-LDL EDTA-sensitive receptor which is suppres sed by casein feeding. Altogether the results are consistent with-the idea that FCE 27677 by acting through inhibition of the cholesterol es terification in the liver normalizes the LDL synthetic rate. ACAT inhi bitors may be useful drugs for the treatment of human dyslipoproteinae mia secondary to derangement of the apoB-100 synthetic rate. (C) 1996 The Italian Pharmacological Society