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ToxSci Advance Access published online on July 12, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn142
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Published by Oxford University Press 2008.

Ligand Activation of Peroxisome Proliferator-activated Receptor-β/{delta} (PPARβ/{delta}) Attenuates Carbon Tetrachloride Hepatotoxicity by Down-regulating Pro-inflammatory Gene Expression

Weiwei Shan*,{dagger}, Prajakta S. Palkar*, Iain A. Murray*, Emily I. McDevitt{ddagger}, Mary J. Kennett*, Boo Hyon Kang§, Harriet C. Isom{ddagger}, Gary H. Perdew*, Frank J. Gonzalez and Jeffrey M. Peters*,{dagger},||

* Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis {dagger} The Intercollege Graduate Degree Program in Genetic, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, PA 16802 {ddagger} Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA 17033 § Non-Clinical Pathology Research Center, Medvill, Seoul, Korea 153-801 Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland 20892

|| To whom correspondence should be addressed: Jeffrey M. Peters, Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802. Tel: (814) 863 1387. Fax: (814) 863-1696. Email: jmp21{at}psu.edu

Received June 10, 2008; revision received July 9, 2008; accepted July 9, 2008


  Abstract

PPARβ/{delta}-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/{delta}-null mice were administered CCl4 with or without co-administration of the highly specific PPARβ/{delta} ligand GW0742. Biomarkers of liver toxicity, including serum alanine aminotransferase (ALT) and hepatic tumor necrosis factor-{alpha} (TNF{alpha}) mRNA, were significantly higher in CCl4-treated PPARβ/{delta}-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 NF-{kappa}B signaling, was higher in the CCl4-treated PPARβ/{delta}-null mice compared to wild-type mice. GW0742 treatment resulted in reduced serum ALT concentration and lower expression of CCl4-induced TNF{alpha}, S100A6, monocyte chemoattractant protein-1 (MCP1) and TWEAKr in wild-type mice, and these effects were not observed in PPARβ/{delta}-null mice. Expression of TNF{alpha} was higher in PPARβ/{delta}-null primary hepatocytes in response to IL-1β treatment compared to wild-type hepatocytes, but GW0742 did not significantly modulate TNF{alpha} expression in hepatocytes from either genotype. While PPARβ/{delta}-null hepatic stellate exhibited higher rates of proliferation compared to wild-type cells, GW0742 did not affect {alpha}-smooth muscle actin ({alpha}SMA) expression in these cells. Combined, these findings demonstrate that ligand activation of PPARβ/{delta} protects against chemically-induced hepatotoxicity by down-regulating expression of pro-inflammatory genes. Hepatocytes and hepatic stellate cells do not appear to directly mediate the inhibitory effects of ligand activation of PPARβ/{delta} in liver, suggesting the involvement of paracrine and autocrine events mediated by hepatic cells.

Key Words: Peroxisome proliferator-activated receptors (PPARs); hepatotoxicity; inflammation.


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