Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity.
Acetaminophen (APAP) overdose causes acute liver failure in humans and rodents due in part to the destruction of mitochondria as a result of increased oxidative stress followed by hepatocellular necrosis. Activation of the peroxisome proliferator-activated receptor alpha (PPARα), a member of the nuclear receptor superfamily that controls the expression of genes encoding peroxisomal and mitochondrial fatty acid β-oxidation enzymes, with the experimental ligand Wy-14,643 or the clinically used fibrate drug fenofibrate, fully protects mice from APAP-induced hepatotoxicity. PPARα-humanized mice were also protected, whereas Ppara-null mice were not, thus indicating that the protection extends to human PPARα and is PPARα-dependent. This protection is due in part to induction of the PPARα target gene encoding mitochondrial uncoupling protein 2 (UCP2). Forced overexpression of UCP2 protected wildtype mice against APAP-induced hepatotoxicity in the absence of PPARα activation. Ucp2-null mice, however, were sensitive to APAP-induced hepatotoxicity despite activation of PPARα with Wy-14,643. Protection against hepatotoxicity by UCP2-induction through activation of PPARα is associated with decreased APAP-induced c-jun and c-fos expression, decreased phosphorylation of JNK and c-jun, lower mitochondrial H(2)O(2) levels, increased mitochondrial glutathione in liver, and decreased levels of circulating fatty acyl-carnitines. These studies indicate that the PPARα target gene UCP2 protects against elevated reactive oxygen species generated during drug-induced hepatotoxicity and suggest that induction of UCP2 may also be a general mechanism for protection of mitochondria during fatty acid β-oxidation.
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA.
Andrew D
AD
Patterson
Yatrik M
YM
Shah
Tsutomu
T
Matsubara
Kristopher W
KW
Krausz
Frank J
FJ
Gonzalez
D000082:Acetaminophen / Q000494:pharmacology / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D047493:PPAR alpha / Q000187:drug effects / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D011897:Random Allocation; D012016:Reference Values; D000071246:Uncoupling Protein 2
D007473:Ion Channels; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D011743:Pyrimidines; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D000082:Acetaminophen; C006253:pirinixic acid