Mechanisms for
hypercholesterolemia and
hypertriglyceridemia and the effects of
KCD-232, a new
hypolipidemic agent, on them were studied in male Wistar rats with
daunorubicin (DR)-induced
nephrosis. Single
intravenous injection of DR dose-dependently increased urinary
protein loss and serum
lipid levels (0,3,6 and 12 mg/kg). Twenty-four days after the injection of DR (6 mg/kg), serum
cholesterol (Ch) and
triglyceride (TG) levels markedly increased and
free fatty acid level tended to decrease with no effects on liver
lipid levels. Hepatic Ch synthesis from [14C]
acetate in vitro increased by 2.1-fold, while exogenous Ch absorption slightly decreased. The clearance of intravenously injected [3H]Ch from the circulation was delayed. Hepatic
fatty acid (FA) synthesis also increased by 2.7-fold, and hepatic TG
lipase activity tended to decrease.
KCD-232 improved the
hypercholesterolemia and
hypertriglyceridemia of DR-treated rats. The
drug inhibited the elevated hepatic Ch synthesis and exogenous Ch absorption and thus improved the delayed Ch clearance from the circulation.
KCD-232 markedly inhibited the elevated hepatic FA synthesis and stimulated both hepatic FA oxidation and
lipoprotein lipase activity from the epididymal adipose tissue of the nephrotic rats. These results suggest that 1. DR-induced
hypercholesterolemia is due to both an increased Ch synthesis in the liver and delayed clearance of Ch from the circulation; 2. DR-induced
hypertriglyceridemia is caused by both an increased hepatic FA synthesis and depressed TG hydrolysis in the circulation; 3.
KCD-232 improves the
hypercholesterolemia by inhibiting the elevated Ch synthesis and Ch absorption from the gut; and 4.
KCD-232 improves the
hypertriglyceridemia by inhibiting the elevated hepatic FA synthesis and by stimulating both hepatic FA oxidation and TG hydrolysis activity in the circulation.