Effect of the peroxisome proliferator LY171883 on triglyceride accumulation in rats fed a fat-free diet.
LY171883 is a leukotriene D4 antagonist that induces peroxisome proliferation in the rodent liver. Like many peroxisome-proliferating agents, it causes transient lipid accumulation and several other changes in hepatic lipid metabolism. The effect of LY171883 on lipid metabolism was studied further in rats maintained on a fat-free diet. Administration of a fat-free diet for 14 days caused a 5.6-fold increase in liver triglycerides associated with a 3.3-fold increase in fatty acid synthetase. Co-administration of 0.1% LY171883 increased liver triglycerides slightly, whereas 0.3% LY171883 prevented the accumulation of triglycerides. Furthermore, treatment with 0.3% LY171883 reversed the fatty liver in rats pretreated with the fat-free diet for 14 days. Fatty acid synthetase activity increased comparably in all treatment groups, indicating that 0.3% LY171883 did not prevent the lipogenic response to a fat-free diet. In rats treated with 0.3% LY171883, peroxisomal beta-oxidation increased 9.5-fold, mitochondrial beta-oxidation 4.8-fold, carnitine palmitoyltransferase I 1.9-fold, and plasma ketones 3-fold. In the 0.1% dose group the increases in these parameters were smaller. The data indicate that 0.3% LY171883 sufficiently increased mitochondrial and peroxisomal beta-oxidation such that fatty acids generated by lipogenesis were preferentially oxidized rather than esterified to triglycerides. In the 0.1% dose group oxidation was only mildly increased, and the excess fatty acids continued to be esterified.
Toxicology Division, Eli Lilly and Company, Greenfield, IN 46140.
P S
PS
Foxworthy
P I
PI
Eacho
D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D004040:Dietary Carbohydrates / Q000494:pharmacology; D004041:Dietary Fats / Q000008:administration & dosage*; D004951:Esterification / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D013777:Tetrazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism*
D000098:Acetophenones; D004040:Dietary Carbohydrates; D004041:Dietary Fats; D005227:Fatty Acids; D013777:Tetrazoles; D014280:Triglycerides; C044660:LY 171883