ToxSci Advance Access published online on May 9, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl002
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1 CIIT Centers for Health Research, Research Triangle Park, North Carolina, 27709; Present address: Division of Endocrine and Metabolic Drug Products, Center for Drug Evaluation and Research, FDA, 5600 Fishers Lane, Rockville, MD 20857
* To whom correspondence should be addressed. Chronic exposure to peroxisome proliferators (PP) leads to increased incidence of liver tumors in rodents. Liver tumor induction is thought to require increased hepatocyte proliferation and suppression of apoptosis. Transcript profiling showed increased expression of pro-apoptotic genes and decreased expression of anti-apoptotic genes in the livers of mice exposed to the PP WY-14,643 (WY). We tested the hypothesis that prior exposure to WY would increase susceptibility to apoptosis inducers such as Jo2, an antibody which activates the Fas (Apo-1/CD95) death pathway. When compared to their untreated counterparts, wild-type mice pretreated with WY exhibited increased caspase-3 activation and hepatocyte apoptosis following challenge with Jo2. Livers from WY-treated PP-activated receptor
Received December 18, 2005
Accepted April 13, 2006
Carcinogenicity
Activation of Peroxisome Proliferator-Activated Receptor alpha (PPAR
Shen Xiao 1,
Steven P. Anderson 2,
Cynthia Swanson 3,
Rainer Bahnemann 4,
Kenneth A. Voss 5,
Anja J. Stauber 6,
and
J. Christopher Corton 3 *
) Enhances Apoptosis in the Mouse Liver
2 Investigative Toxicology and Pathology Group, Safety Assessment, GlaxoSmithKline Research & Development, Research Triangle Park, NC 27709-3998; Present address: Bayer Corporation, 85 T.W. Alexander Drive, Research Triangle Park, NC 27709
3 CIIT Centers for Health Research, Research Triangle Park, North Carolina, 27709
4 Department of Toxicology, BASF Aktiengesellschaft, Ludwigshafen, Germany
5 USDA, Athens, GA 30604-5677
6 CIIT Centers for Health Research, Research Triangle Park, North Carolina, 27709; Present address: Lilly Research Laboratories, 2001 West Main Street, Greenfield, IN 46140
J. Christopher Corton, E-mail: corton.chris{at}epa.gov
Abstract 
(PPAR)-null mice were resistant to the effects of Jo2. In the absence of Jo2 and detectable apoptosis, wild-type mice treated with WY exhibited increases in the activated form of caspase-9. As caspase-9 is a component of the apoptosome, we examined the expression of upstream effectors of apoptosome activity including members of the Bcl-2 family. The levels of the anti-apoptotic Mcl-1 transcript and protein were significantly decreased by PP. PPAR-null mice were also resistant to another treatment (conconavalin A) that induces hepatocyte apoptosis. These results 1) indicate that PPAR activation increases sensitivity of the liver to apoptosis and 2) identify a mechanism by which PPAR could serve as a pharmacological target in diseases where apoptosis is a contributing feature.
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