Changes in hepatic lipid metabolism associated with lipid accumulation and its reversal in rats given the peroxisome proliferator LY171883.
Dietary administration of 0.05, 0.1, and 0.3% LY171883 to rats for 1 day caused a dose-related increase in hepatic triglycerides. When added to rat liver mitochondria in vitro, LY171883 caused competitive inhibition of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting enzyme for mitochondrial fatty acid oxidation. This effect appears to be involved in the lipid accumulation. The hepatic triglycerides in rats given 0.1% LY171883 increased progressively through 3 months of treatment. In contrast, hepatic triglycerides in high-dose rats returned to control levels by Day 3 and remained there throughout the study. The regression of the lipid corresponded with increases in hepatic peroxisomal beta-oxidation, mitochondrial beta-oxidation, and CPT-1 activity of up to 13-, 7-, and 3.2-fold, respectively. The 0.1% dose increased these parameters modestly compared to those of high-dose rats (2-, 3-, and 1.6-fold, respectively). Addition of LY171883 to mitochondria from rats given dietary treatment for 2 weeks inhibited CPT-I by the same percentage as in control mitochondria. In mid-dose rats, the induction of CPT-I was largely negated by LY171883 in vitro. Even with the inhibition, CPT-I activity in mitochondria from high-dose rats remained 2-fold higher than that in untreated controls. The data suggest that the induction of CPT-I in high-dose rats was sufficient to overcome the inhibitory action of LY171883. The increased oxidative capacity in peroxisomes and mitochondria led to the regression of the lipid in high-dose rats. The more modest increases in fatty acid oxidation in rats given 0.1% LY171883 were not sufficient to reverse the lipid accumulation.
Foxworthy
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Toxicology Division, Eli Lilly and Company, Greenfield, Indiana 46140.
Perry
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Hoover
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Eacho
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D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D012898:Autacoids / Q000037:antagonists & inhibitors*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D005227:Fatty Acids / Q000378:metabolism; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D013777:Tetrazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism
D000098:Acetophenones; D012898:Autacoids; D005227:Fatty Acids; D013777:Tetrazoles; D014280:Triglycerides; C044660:LY 171883; D002334:Carnitine O-Palmitoyltransferase