TY - JOUR T1 - Disruption of Hepatic Lipid Homeostasis in Mice after Amiodarone Treatment Is Associated with Peroxisome Proliferator-Activated Receptor-αTarget Gene Activation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 864 LP - 873 DO - 10.1124/jpet.104.072785 VL - 311 IS - 3 AU - Tanya C. McCarthy AU - P. Timothy Pollak AU - Elyisha A. Hanniman AU - Christopher J. Sinal Y1 - 2004/12/01 UR - http://jpet.aspetjournals.org/content/311/3/864.abstract N2 - Amiodarone, an efficacious and widely used antiarrhythmic agent, has been reported to cause hepatotoxicity in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of amiodarone and examined for changes in hepatic histology and gene regulation. Amiodarone induced hepatomegaly, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum triglycerides and glucose. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for fatty acid oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor-α (PPARα), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPARα knockout [PPARα(—/—)] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPARα gene. Compared to wild-type mice, treatment of PPARα(—/—) mice with amiodarone resulted in an increased rate and extent of total body weight loss. The inability of amiodarone to directly activate either human or mouse PPARα transiently expressed in human HepG2 hepatoma cells indicates that the effects of amiodarone on the function of this receptor were indirect. Based upon these results, we conclude that amiodarone disrupts hepatic lipid homeostasis and that the increased expression of PPARα target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPARα protects against amiodarone-induced hepatotoxicity. The American Society for Pharmacology and Experimental Therapeutics ER -