Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation.
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-alpha (PPARalpha), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPARalpha knockout [PPARalpha-/-] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPARalpha gene. Compared to wild-type mice, treatment of PPARalpha-/- 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 PPARalpha 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 PPARalpha target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPARalpha protects against amiodarone-induced hepatotoxicity.
McCarthy
Tanya C
TC
Department of Pharmacology, Sir Charles Tupper Medical Building, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5.
Pollak
P Timothy
PT
Hanniman
Elyisha A
EA
Sinal
Christopher J
CJ
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006529:Hepatomegaly / Q000139:chemically induced; D006706:Homeostasis / Q000187:drug effects*; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D000889:Anti-Arrhythmia Agents; D001786:Blood Glucose; D047493:PPAR alpha; C036116:desethylamiodarone; D000638:Amiodarone