Differential effects of beclobrate on lipid/lipoprotein distribution in normal and hypercholesterolemic rats

Beclobrate, a new fibric acid derivative, displays remarkable lipid lowering activity in rodents. In order to evaluate changes in the distribution and liver handling of lipoproteins, beclobrate was tested in rats fed on a normal or hypercholesterolemic diet. On the normal diet, beclobrate lowered total plasma cholesterol by 22-33.4% (10-50 mg/kg); the cholesterol reduction occurred mainly in high density lipoproteins (HDL) (by 24-45% with the three tested doses). The metabolic clearance of 125I-labelled beta-very low density lipoproteins (beta-VLDL) injected into these animals almost doubled (0.20 1/h vs. 0.13 1/h in controls) after treatment with 20 mg/kg of beclobrate. In addition, beclobrate administration dramatically increased the activity of the high-affinity receptors for beta-VLDL in isolated liver membranes (Bmax: 208 +/- 17.6 vs. 146 +/- 2.6 ng/mg of protein for controls). On the hypercholesterolemic diet, beclobrate treatment (50 mg/kg) was associated with a 25% reduction in total cholesterol accompanied, however, by a 166% rise in HDL cholesterol. In these animals, the composition of VLDL, typically cholesterol-enriched, became close to normal. The increased HDL was characterized by a remarkable enrichment with particles containing apolipoprotein E (apo E), which is compatible with either an improved peripheral cholesterol removal or an enhanced direct secretion of apo E. The two models offer different opportunities for evaluating the mechanism of action of this new lipid lowering agent. Lipoprotein catabolism and receptor-mediated clearance were characteristically improved in normolipidemic rats whereas major effects on HDL metabolism could be demonstrated in hypercholesterolemic rats.