ToxSci Advance Access originally published online on May 9, 2006
Toxicological Sciences 2006 92(2):368-377; doi:10.1093/toxsci/kfl002
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Activation of Peroxisome Proliferator–Activated Receptor Alpha Enhances Apoptosis in the Mouse Liver
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* CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709; Investigative Toxicology and Pathology Group, Safety Assessment, GlaxoSmithKline Research & Development, Research Triangle Park, North Carolina 27709-3998; Department of Toxicology, BASF Aktiengesellschaft, Ludwigshafen, Germany; and USDA, Athens, Georgia 30604-5677
Received December 18, 2005; accepted April 13, 2006
Chronic exposure to peroxisome proliferators (PPs) 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 proapoptotic genes and decreased expression of antiapoptotic 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 peroxisome proliferator–activated receptor alpha (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 antiapoptotic Mcl-1 transcript and protein were significantly decreased by PPs. PPAR-null mice were also resistant to another treatment (concanavalin 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.
Key Words: peroxisome proliferators; liver tumor; hepatocyte proliferation; apoptosis; caspase.