Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity.

Abstract

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.

• Authors: Andrew D Patterson, Yatrik M Shah, Tsutomu Matsubara, Kristopher W Krausz, Frank J Gonzalez
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 56 Issue 1 Pg. 281-90 (Jul 2012) ISSN: 1527-3350 [Electronic] United States
• PMID: 22318764 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2012 American Association for the Study of Liver Diseases.

Chemical References

• Ion Channels
• Mitochondrial Proteins
• PPAR alpha
• Pyrimidines
• UCP2 protein, human
• Ucp2 protein, mouse
• Uncoupling Protein 2
• Acetaminophen
• pirinixic acid

Topics

• Acetaminophen (pharmacology, toxicity)
• Analysis of Variance
• Animals
• Blotting, Western
• Chemical and Drug Induced Liver Injury (etiology, pathology, prevention & control)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Immunohistochemistry
• Injections, Intraperitoneal
• Ion Channels (drug effects, metabolism)
• Liver (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondrial Proteins (drug effects, metabolism)
• Oxidative Stress (drug effects, physiology)
• PPAR alpha (drug effects, metabolism)
• Pyrimidines (pharmacology)
• Random Allocation
• Reference Values
• Uncoupling Protein 2