ToxSci Advance Access originally published online on July 12, 2008
Toxicological Sciences 2008 105(2):418-428; doi:10.1093/toxsci/kfn142
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Published by Oxford University Press 2008.
Ligand Activation of Peroxisome Proliferator–Activated Receptor β/
(PPARβ/) Attenuates Carbon Tetrachloride Hepatotoxicity by Downregulating Proinflammatory Gene Expression
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* Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802
The Intercollege Graduate Degree Program in Genetic, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802
Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, Pennsylvania 17033
Non-Clinical Pathology Research Center, Medvill, Seoul, Korea 153-801
¶ Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland 20892
1 To whom correspondence should be addressed. Fax: (814) 863-1696. E-mail: jmp21{at}psu.edu.
Received June 10, 2008; accepted July 9, 2008
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Abstract |
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Peroxisome proliferator–activated receptor (PPAR) β/
–null mice exhibit exacerbated hepatotoxicity in response to administration of carbon tetrachloride (CCl4). To determine whether ligand activation of the receptor protects against chemical toxicity in the liver, wild-type and PPARβ/-null mice were administered CCl4 with or without coadministration of the highly specific PPARβ/ ligand GW0742. Biomarkers of liver toxicity, including serum alanine aminotransferase (ALT) and hepatic tumor necrosis factor (TNF) 
mRNA, were significantly higher in CCl4-treated PPARβ/-null mice compared to wild-type mice. Hepatic expression of TNF-like weak inducer of apoptosis receptor (TWEAKr) and S100 calcium–binding protein A6 (S100A6/calcyclin), genes involved in nuclear factor kappa B signaling, was higher in the CCl4-treated PPARβ/-null mice compared to wild-type mice. GW0742 treatment resulted in reduced serum ALT concentration and lower expression of CCl4-induced TNF-, S100A6, monocyte chemoattractant protein-1 (MCP1), and TWEAKr in wild-type mice, and these effects were not observed in PPARβ/-null mice. Expression of TNF- was higher in PPARβ/-null primary hepatocytes in response to interleukin-1β treatment compared to wild-type hepatocytes, but GW0742 did not significantly modulate TNF- expression in hepatocytes from either genotype. While PPARβ/-null hepatic stellate exhibited higher rates of proliferation compared to wild-type cells, GW0742 did not affect -smooth muscle actin expression in these cells. Combined, these findings demonstrate that ligand activation of PPARβ/ protects against chemically induced hepatotoxicity by downregulating expression of proinflammatory genes. Hepatocytes and hepatic stellate cells do not appear to directly mediate the inhibitory effects of ligand activation of PPARβ/ in liver, suggesting the involvement of paracrine and autocrine events mediated by hepatic cells.
Key Words: peroxisome proliferator–activated receptors; hepatotoxicity; inflammation.