HOE 402 lowers serum cholesterol levels by reducing VLDL-lipid production, and not by induction of the LDL receptor, and reduces atherosclerosis in wild-type and LDL receptor-deficient mice.
Previous rodent studies suggested that the potent hypolipidemic agent 4-amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)pyrimidine-5-N-(trifluoromethyl-phenyl) carboxamide monohydrochloride (HOE 402) is an inducer of the LDL receptor (LDLR). Using wild-type and heterozygous and homozygous LDLR-deficient (LDLR+/0 and LDLR0/0) mice, fed a low or high cholesterol diet, we investigated whether HOE 402 specifically induces the LDLR and whether other pathways are affected. Upon treatment with 0.05% (w/w) HOE 402, the serum cholesterol levels of wild-type, LDLR+/0 and LDLR0/0 mice, were maximally reduced by 53, 56, and 73%, respectively (P<0.05), by reducing levels in very low density-lipoprotein (VLDL), intermediate density-lipoprotein (IDL), and low density-lipoprotein (LDL) cholesterol, whereas high density-lipoprotein (HDL) cholesterol levels were increased. The observations that HOE 402 exhibited no effect on in vivo clearance of 125I-labeled LDL in wild-type mice, and clearly reduced serum cholesterol levels in LDLR0/0 mice, indicate that the LDLR is not the main target for the compound. In wild-type mice, production of VLDL-TG, and cholesterol were reduced by more than 50% by HOE 402 (P<0.05), whereas VLDL apolipoprotein B (ApoB) secretion was unaffected, indicating that HOE 402 treatment changes the size, rather than the number of the secreted VLDL particles. The reduced VLDL production was accompanied by a 22% decreased hepatic cholesterol ester concentration (P<0.05). Additionally, HOE 402 treatment strongly reduced the aortic content of atherosclerotic lesions by 90 and 72% in LDLR+/0 and LDLR0/0 mice, respectively (P<0.01). In conclusion, HOE 402 is a potent cholesterol-lowering compound, which inhibits VLDL production, and consequently attenuates atherosclerosis development.
Draijer
Richard
R
Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands.
Volger
Oscar L
OL
Dahlmans
Vivian E H
VE
de Wit
Elly C M
EC
Havekes
Louis M
LM
Princen
Hans M G
HM
D000818:Animals; D001011:Aorta / Q000473:pathology; D001161:Arteriosclerosis / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood*; D004195:Disease Models, Animal; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D007093:Imidazoles / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011743:Pyrimidines / Q000627:therapeutic use*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
D000960:Hypolipidemic Agents; D007093:Imidazoles; D008055:Lipids; D008079:Lipoproteins, VLDL; D011743:Pyrimidines; D011973:Receptors, LDL; C081893:HOE 402; D002784:Cholesterol