[Experimental nephrotic hyperlipidemia induced in rats by daunorubicin and effects of KCD-232[4-(4'-chlorobenzyloxy)benzyl nicotinate] on lipid metabolism].
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.
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003630:Daunorubicin / Q000037:antagonists & inhibitors*; D006949:Hyperlipidemias / Q000139:chemically induced / Q000188:drug therapy*; D000960:Hypolipidemic Agents; D007408:Intestinal Absorption; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009401:Nephrosis / Q000139:chemically induced / Q000188:drug therapy*; D009539:Nicotinic Acids / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains
D000960:Hypolipidemic Agents; D009539:Nicotinic Acids; C042413:4-(4'-chlorobenzyloxy)benzyl nicotinate; D003630:Daunorubicin