Hypolipidemic activity of HOE-402 is mediated by stimulation of the LDL receptor pathway

HOE-402 (4-amino-2-[4,4-dimethyl-2-oxo-1-imidazolidinyl]-pyrimidine-5-N- [trifluoromethylphenyl]-carboxamide-monohydrochloride) has been shown to exhibit hypolipidemic action in heterozygous Watanabe heritable hyperlipidemic rabbits. In all animals, elevated cholesterol levels were reduced to normal (from 3.0 to 1.5 mmol/L) after 3 weeks of HOE-402 treatment. This was due entirely to reduction of low density lipoprotein (LDL) cholesterol and was paralleled by accelerated removal of plasma 125I-LDL. This reduction of LDL levels was not found in homozygous LDL receptor-defective animals, emphasizing the necessity of a functional LDL receptor system for the hypolipidemic action. The effect of HOE-402 on LDL receptor activity in the cultured hepatoma cell line HepG2 was also determined. When cells were incubated with plasma from treated animals (containing cholesterol 1.5 mmol/L and HOE-402 80 ng/mL), high-affinity cell-surface binding sites for LDL were induced more than threefold, as shown by Scatchard analysis of cell-surface binding data. Induction of the LDL receptor was detectable after 6 hours and was 300% after 18 hours. This induction was specific for LDL, as 125I-transferrin and [59Fe]transferrin were internalized normally in HOE-402-treated cells. The increase of LDL receptor protein was related to induced LDL receptor mRNA levels (400%), as shown by quantification of Northern blotting experiments. These findings suggest that HOE-402 mediated its hypolipidemic action mainly via the LDL receptor pathway. It enhanced mRNA levels for LDL receptor, hence increasing its synthesis, which subsequently resulted in reduced plasma LDL levels.