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United States Department of Agriculture

Agricultural Research Service


item Xiao, S
item Anderson, S
item Swanson, C
item Bahnemann, R
item Voss, Kenneth - Ken
item Stauber, A
item Corton, J

Submitted to: Toxicological Sciences
Publication Type: Abstract Only
Publication Acceptance Date: 1/30/2005
Publication Date: 3/15/2005
Citation: Xiao, S., Anderson, S.P., Swanson, C., Bahnemann, R., Voss, K.A., Stauber, A.J., Corton, J.C. 2005. Activation of peroxisome proliferator-activated receptor alpha enhances hepatocyte apoptosis. Toxicological Sciences. 84(S1):469.

Interpretive Summary: Abstract - no summary

Technical Abstract: 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-apoptosis genes and decreased expression of anti-apoptotic genes in the livers of mice exposed to the PP WY14, 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 alpha (PPAR alpha)-null mice were resistant to the effects of Jo2. In the absence of Jo2, 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. Only the levels of the anti-apoptotic Mcl-1 transcript and protein were significantly altered by PP. The effects of PPARalpha activation on apoptosis were not specific to Jo2 as PPARalpha-null mice were also resistant to another treatment that induces hepatocyte apoptosis. Theses results 1) demonstrate PPARalpha activation increases sensitivity of hepatocytes to apoptosis, 2) imply that PP exposure does not consistently lead to suppression of apoptosis in hepatocarcinogenesis and 3) indentify a mechanism by which PPARalpha could serve as a pharmacological target in diseases where apoptosis is a contributing feature.

Last Modified: 10/19/2017
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